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Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights

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Abstract

Oral squamous cell carcinoma (OSCC) is a cancer type with a high rate of recurrence and a poor prognosis. Tumor chemo-resistance remains an issue for OSCC patients despite the availability of multimodal therapy options, which causes an increase in tumor invasiveness. Vacuolar ATPase (V-ATPase), appears to be one of the most significant molecules implicated in MDR in tumors like OSCC. It is primarily responsible for controlling the acidity in the solid tumors’ microenvironment, which interferes with the absorption of chemotherapeutic medications. However, the exact cellular and molecular mechanisms V-ATPase plays in OSCC chemo-resistance have not been understood. Uncovering these mechanisms can contribute to combating OSCC chemo-resistance and poor prognosis. Hence, in this review, we suggest that one of these underlying mechanisms is autophagy induced by V-ATPase which can potentially contribute to OSCC chemo-resistance. Finally, specialized autophagy and V-ATPase inhibitors may be beneficial as an approach to reduce drug resistance to anticancer therapies in addition to serving as coadjuvants in antitumor treatments. Also, V-ATPase could be a prognostic factor for OSCC patients. However, in the future, more investigations are required to demonstrate these suggestions and hypotheses.

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References

  1. Norouzi A, Davodabadi F, Noorbakhsh Varnosfaderani SM, Zalpoor H. The potential role of acid ceramidase in oral squamous cell carcinoma chemo-resistance by inducing autophagy. Hum Cell. 2023. https://doi.org/10.1007/s13577-023-00960-0.

    Article  PubMed  Google Scholar 

  2. El Sheikh M. Survival and quality of life for Sudanese oral cancer patients: University College Cork; 2018.

  3. Johnson NW, Gupta B, Speicher DJ, Ray CS, Shaikh MH, Al-Hebshi N, et al. Etiology and risk factors. Oral and oropharyngeal cancer: CRC Press; 2018. p. 19–94.

    Google Scholar 

  4. Tangsiri M, Hheidari A, Liaghat M, Razlansari M, Ebrahimi N, Akbari A, et al. Promising applications of nanotechnology in inhibiting chemo-resistance in solid tumors by targeting epithelial-mesenchymal transition (EMT). Biomed Pharmacother. 2024;170: 115973.

    Article  CAS  PubMed  Google Scholar 

  5. Chaturvedi P, Singhavi H, Malik A, Nair D. Outcome of head and neck squamous cell cancers in low-resource settings: Challenges and opportunities. Otolaryngol Clin North Am. 2018;51(3):619–29.

    Article  PubMed  Google Scholar 

  6. Saalim M, Sansare K, Karjodkar FR, Johaley S, Ali IK, Sharma SR, et al. The prevalence of oral squamous cell carcinoma with oral submucous fibrosis. J Cancer Res Ther. 2021;17(6):1510–4.

    Article  PubMed  Google Scholar 

  7. Panarese I, Aquino G, Ronchi A, Longo F, Montella M, Cozzolino I, et al. Oral and Oropharyngeal squamous cell carcinoma: prognostic and predictive parameters in the etiopathogenetic route. Expert Rev Anticancer Ther. 2019;19(2):105–19.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang J, Shen Q, Ma Y, Liu L, Jia W, Chen L, et al. Calcium Homeostasis in Parkinson’s Disease: From Pathology to Treatment. Neurosci Bull. 2022;38(10):1267–1270. https://doi.org/10.1007/s12264-022-00899-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhu Y, Huang R, Wu Z, Song S, Cheng L, Zhu R. Deep learning-based predictive identification of neural stem cell differentiation. Nat Commun. 2021;12(1):2614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cheng Y, Li S, Gao L, Zhi K, Ren W. The molecular basis and therapeutic aspects of cisplatin resistance in oral squamous cell carcinoma. Front Oncol. 2021;11: 761379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pan L, Feng F, Wu J, Fan S, Han J, Wang S, et al. Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells. Pharmacol Res. 2022;181: 106270.

    Article  CAS  PubMed  Google Scholar 

  12. Xu H, Li L, Wang S, Wang Z, Qu L, Wang C, et al. Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Phytomedicine. 2023:154940.

  13. Sharma M, Astekar M, Soi S, S Manjunatha B, C Shetty D, Radhakrishnan R. pH gradient reversal: an emerging hallmark of cancers. Recent patents on anti-cancer drug discovery. 2015;10(3):244–58.

  14. Gan Y, Xu Y, Zhang X, Hu H, Xiao W, Yu Z, et al. Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation. Molecules. 2023;28(19):6962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Otero-Rey EM, Somoza-Martín M, Barros-Angueira F, García-García A. Intracellular pH regulation in oral squamous cell carcinoma is mediated by increased V-ATPase activity via over-expression of the ATP6V1C1 gene. Oral Oncol. 2008;44(2):193–9.

    Article  CAS  PubMed  Google Scholar 

  16. Eaton AF, Merkulova M, Brown D. The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease. Am J Physiol Cell Physiol. 2021;320(3):C392–414.

    Article  CAS  PubMed  Google Scholar 

  17. Chen F, Kang R, Liu J, Tang D. The V-ATPases in cancer and cell death. Cancer Gene Ther. 2022;29(11):1529–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang A, Zhou W. Mn-based cGAS-STING activation for tumor therapy. Chin J Cancer Res. 2023;35(1):19–43. https://doi.org/10.21147/j.issn.1000-9604.2023.01.04

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao Y, Liu Y, Liu Y, Peng Y, Yuan B, Fu Y, et al. UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications. Cancer Lett. 2021;520:172–183.

    Article  CAS  PubMed  Google Scholar 

  20. Hraběta J, Belhajová M, Šubrtová H, Merlos Rodrigo MA, Heger Z, Eckschlager T. Drug sequestration in lysosomes as one of the mechanisms of chemoresistance of cancer cells and the possibilities of its inhibition. Int J Mol Sci. 2020;21(12):4392.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang Y, Zhang L, Wei Y, Huang W, Li L, Wu A-a, et al. Pharmacological targeting of vacuolar H+-ATPase via subunit V1G combats multidrug-resistant cancer. Cell Chem Biol. 2020;27(11):1359.

  22. Law Z-J, Khoo XH, Lim PT, Goh BH, Ming LC, Lee W-L, et al. Extracellular vesicle-mediated chemoresistance in oral squamous cell carcinoma. Front Mol Biosci. 2021;8: 629888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kiyoshima T, Yoshida H, Wada H, Nagata K, Fujiwara H, Kihara M, et al. Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression. PLoS ONE. 2013;8(11): e80998.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Dong Y, Zhu G, Wang S-F, Keon KA, Rubinstein JL, Zeng S-X, et al. Toosendanin, a novel potent vacuolar-type H+-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy. Int J Biol Sci. 2022;18(7):2684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang Y, Mengnan Z, Benke L, Zhang B, Bing C, Yuanyuan W, et al. Ephedra Herb extract ameliorates adriamycin-induced nephrotic syndrome in rats via the CAMKK2/AMPK/mTOR signaling pathway. Chin J Nat Med. 2023;21(5):371–82.

    CAS  PubMed  Google Scholar 

  26. Kulshrestha A, Katara GK, Ibrahim SA, Riehl VE, Schneiderman S, Bilal M, et al. In vivo anti-V-ATPase antibody treatment delays ovarian tumor growth by increasing antitumor immune responses. Mol Oncol. 2020;14(10):2436–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhu L, Smith PP, Boyes SG. pH-responsive polymers for imaging acidic biological environments in tumors. J Polym Sci B Polym Phys. 2013;51:1062.

    Article  CAS  Google Scholar 

  28. de Bem PB, Nunes JS, da Silva VP, Laureano NK, Gonçalves DR, Machado IS, et al. The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma. Life Sci. 2022;288: 120163.

    Article  Google Scholar 

  29. Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars Cancer Biol. 2017;43:74.

    Article  CAS  Google Scholar 

  30. Alshaker HA, Matalka KZ. IFN-γ, IL-17 and TGF-β involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors. Cancer Cell Int. 2011;11(1):1–12.

    Article  Google Scholar 

  31. Rahat MA, Hemmerlein B. Macrophage-tumor cell interactions regulate the function of nitric oxide. Front Physiol. 2013;4:144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mostafavi S, Zalpoor H, Hassan ZM. The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors. Cell Mol Biol Lett. 2022;27(1):1–24.

    Article  Google Scholar 

  33. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Can Res. 2016;76(6):1381–90.

    Article  CAS  Google Scholar 

  34. Tong L, Yue P, Yang Y, Huang J, Zeng Z, Qiu W. Motility and mechanical properties of dendritic cells deteriorated by extracellular acidosis. Inflammation. 2021;44:737–45.

    Article  CAS  PubMed  Google Scholar 

  35. Worsley CM, Veale RB, Mayne ES. The acidic tumour microenvironment: Manipulating the immune response to elicit escape. Hum Immunol. 2022;83(5):399–408.

    Article  CAS  PubMed  Google Scholar 

  36. Cao J, Chen C, Wang Y, Chen X, Chen Z, Luo X. Influence of autologous dendritic cells on cytokine-induced killer cell proliferation, cell phenotype and antitumor activity in vitro. Oncol Lett. 2016;12(3):2033–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen L, He Y, Zhu J, Zhao S, Qi S, Chen X, et al. The roles and mechanism of m6A RNA methylation regulators in cancer immunity. Biomed Pharmacother. 2023;163: 114839.

    Article  CAS  PubMed  Google Scholar 

  38. Lv C, Yang X, Yu B, Ma Q, Liu B, Liu Y. Blocking the Na+/H+ exchanger 1 with cariporide (HOE642) reduces the hypoxia-induced invasion of human tongue squamous cell carcinoma. Int J Oral Maxillofac Surg. 2012;41(10):1206–10.

    Article  CAS  PubMed  Google Scholar 

  39. Zhou J, Guo T, Zhou L, Bao M, Wang L, Zhou W, et al. The ferroptosis signature predicts the prognosis and immune microenvironment of nasopharyngeal carcinoma. Sci Rep. 2023;13(1):1861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hu J, Li G, Liu Z, Ma H, Yuan W, Lu Z, et al. Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway. Mol Carcinogenesis. 2023;62:628.

    Article  CAS  Google Scholar 

  41. Swenson ER. Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol. 2006;151(2–3):209–16.

    Article  CAS  PubMed  Google Scholar 

  42. Chu Y-H, Su C-W, Hsieh Y-S, Chen P-N, Lin C-W, Yang S-F. Carbonic anhydrase III promotes cell migration and epithelial-mesenchymal transition in oral squamous cell carcinoma. Cells. 2020;9(3):704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ivanov S, Liao S-Y, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, et al. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol. 2001;158(3):905–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Choi S-W, Kim J-Y, Park J-Y, Cha I-H, Kim J, Lee S. Expression of carbonic anhydrase IX is associated with postoperative recurrence and poor prognosis in surgically treated oral squamous cell carcinoma. Hum Pathol. 2008;39(9):1317–22.

    Article  CAS  PubMed  Google Scholar 

  45. Akocak S, Güzel-Akdemir Ö, Sanku RKK, Russom SS, Iorga BI, Supuran CT, et al. Pyridinium derivatives of 3-aminobenzenesulfonamide are nanomolar-potent inhibitors of tumor-expressed carbonic anhydrase isozymes CA IX and CA XII. Bioorg Chem. 2020;103: 104204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ivanov SV, Kuzmin I, Wei M-H, Pack S, Geil L, Johnson BE, et al. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci. 1998;95(21):12596–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos K, Pastorek J, Wykoff CC, et al. Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res. 2001;7(11):3399–403.

    CAS  PubMed  Google Scholar 

  48. Hedley D, Pintilie M, Woo J, Morrison A, Birle D, Fyles A, et al. Carbonic anhydrase IX expression, hypoxia, and prognosis in patients with uterine cervical carcinomas. Clin Cancer Res. 2003;9(15):5666–74.

    CAS  PubMed  Google Scholar 

  49. Daunys S, Petrikaitė V. The roles of carbonic anhydrases IX and XII in cancer cell adhesion, migration, invasion and metastasis. Biol Cell. 2020;112(12):383–97.

    Article  CAS  PubMed  Google Scholar 

  50. Chien M-H, Ying T-H, Hsieh Y-H, Lin C-H, Shih C-H, Wei L-H, et al. Tumor-associated carbonic anhydrase XII is linked to the growth of primary oral squamous cell carcinoma and its poor prognosis. Oral Oncol. 2012;48(5):417–23.

    Article  CAS  PubMed  Google Scholar 

  51. Pamarthy S, Kulshrestha A, Katara GK, Beaman KD. The curious case of vacuolar ATPase: regulation of signaling pathways. Mol Cancer. 2018;17:1–9.

    Article  Google Scholar 

  52. Huang L, Lu Q, Han Y, Li Z, Zhang Z, Li X. ABCG2/V-ATPase was associated with the drug resistance and tumor metastasis of esophageal squamous cancer cells. Diagn Pathol. 2012;7(1):1–7.

    Article  Google Scholar 

  53. Pérez-Sayáns M, Somoza-Martín JM, Barros-Angueira F, Diz PG, Rey JMG, García-García A. Multidrug resistance in oral squamous cell carcinoma: the role of vacuolar ATPases. Cancer Lett. 2010;295(2):135–43.

    Article  PubMed  Google Scholar 

  54. Ghaly AM, Elshenshawy HMA, Abd El Hafez A, Ibrahim MMA, El-Sissi AAI. The prognostic role of hypoxia and the microenvironmental acidity in chemo-radio resistance in oral squamous cell carcinoma patients. Acta Biomed. 2023;94(3):e20237114.

  55. Logozzi M, Spugnini E, Mizzoni D, Di Raimo R, Fais S. Extracellular acidity and increased exosome release as key phenotypes of malignant tumors. Cancer Metastasis Rev. 2019;38:93–101.

    Article  CAS  PubMed  Google Scholar 

  56. Pérez-Sayáns M, García-García A, Reboiras-López MD, Gándara-Vila P. Role of V-ATPases in solid tumors: importance of the subunit C. Int J Oncol. 2009;34(6):1513–20.

    Article  PubMed  Google Scholar 

  57. Kobliakov V. The role of extra-and intracellular pH values in regulation of the tumor process. Cell and Tissue Biology. 2022;16(2):114–20.

    Article  CAS  Google Scholar 

  58. Zheng T, Jäättelä M, Liu B. pH gradient reversal fuels cancer progression. Int J Biochem Cell Biol. 2020;125: 105796.

    Article  CAS  PubMed  Google Scholar 

  59. Whitton B. Investigating the role of vacuolar-ATPase (V-ATPase) in cancer: University of Southampton; 2020.

  60. Sennoune SR, Bakunts K, Martínez GM, Chua-Tuan JL, Kebir Y, Attaya MN, et al. Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol Cell Physiol. 2004;286(6):C1443–52.

    Article  CAS  PubMed  Google Scholar 

  61. Capecci J. Function of Plasma Membrane V-ATPases in Breast Tumor Cell Invasion: Tufts University-Graduate School of Biomedical Sciences; 2014.

  62. Nishi T, Forgac M. The vacuolar (H+)-ATPases—nature’s most versatile proton pumps. Nat Rev Mol Cell Biol. 2002;3(2):94–103.

    Article  CAS  PubMed  Google Scholar 

  63. Su KL. The Role of Plasma Membrane V-ATPases in Breast Cancer Metastasis: Tufts University-Graduate School of Biomedical Sciences; 2021.

  64. Boedtkjer E. Ion channels, transporters, and sensors interact with the acidic tumor microenvironment to modify cancer progression. From Malignant Transformation to Metastasis: Ion Transport in Tumor Biology. 2021:39–84.

  65. Di Pompo G, Cortini M, Baldini N, Avnet S. Acid microenvironment in bone sarcomas Cancers. 2021;13(15):3848.

    PubMed  Google Scholar 

  66. Fliegel L. Role of pH regulatory proteins and dysregulation of pH in prostate cancer. From Malignant Transformation to Metastasis: Ion Transport in Tumor Biology. 2020:85–110.

  67. Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H. The cellular biology of proton-motive force generation by V-ATPases. J Exp Biol. 2000;203(1):89–95.

    Article  CAS  PubMed  Google Scholar 

  68. Damaghi M, Wojtkowiak JW, Gillies RJ. pH sensing and regulation in cancer. Front Physiol. 2013;4:370.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Swietach P. What is pH regulation, and why do cancer cells need it? Cancer Metastasis Rev. 2019;38:5–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thews O, Riemann A. Tumor pH and metastasis: a malignant process beyond hypoxia. Cancer Metastasis Rev. 2019;38:113–29.

    Article  CAS  PubMed  Google Scholar 

  71. Li L, Wang S, Zhou W. Balance cell apoptosis and pyroptosis of caspase-3-activating chemotherapy for better antitumor therapy. Cancers. 2022;15(1):26.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Lorenzo Pouso AI, González-Moles MÁ, Ramos-García P, Pérez SM. The Immunohistochemical Landscape of the Hypoxia-Related Proteins in Oral Squamous Cell Carcinoma. Cham: Springer; 2022.

    Book  Google Scholar 

  73. Lorenzo-Pouso AI, Castelo-Baz P, Pérez-Sayáns M, Lim J, Leira Y. Autophagy in periodontal disease: Evidence from a literature review. Arch Oral Biol. 2019;102:55–64.

    Article  CAS  PubMed  Google Scholar 

  74. Vitavska O, Wieczorek H, Merzendorfer H. A novel role for subunit C in mediating binding of the H+-V-ATPase to the actin cytoskeleton. J Biol Chem. 2003;278(20):18499–505.

    Article  CAS  PubMed  Google Scholar 

  75. Tripathi A, Misra S. Vacuolar ATPase (V-ATPase) Proton Pump and Its Significance in Human Health. Ion Transporters-From Basic Properties to Medical Treatment: IntechOpen; 2022.

  76. Sennoune SR, Martinez-Zaguilan R. Plasmalemmal vacuolar H+-ATPases in angiogenesis, diabetes and cancer. J Bioenerg Biomembr. 2007;39:427–33.

    Article  CAS  PubMed  Google Scholar 

  77. Vaidya FU, Sufiyan Chhipa A, Mishra V, Gupta VK, Rawat SG, Kumar A, et al. Molecular and cellular paradigms of multidrug resistance in cancer. Cancer Reports. 2022;5(12): e1291.

    Article  CAS  PubMed  Google Scholar 

  78. Seebacher NA, Krchniakova M, Stacy AE, Skoda J, Jansson PJ. Tumour microenvironment stress promotes the development of drug resistance. Antioxidants. 2021;10(11):1801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pérez-Sayáns M, Somoza-Martín JM, Barros-Angueira F, Rey JMG, García-García A. V-ATPase inhibitors and implication in cancer treatment. Cancer Treat Rev. 2009;35(8):707–13.

    Article  PubMed  Google Scholar 

  80. Becelli R, Renzi G, Morello R, Altieri F. Intracellular and extracellular tumor pH measurement in a series of patients with oral cancer. J Craniofacial Surg. 2007;18(5):1051–4.

    Article  Google Scholar 

  81. Hamm R, Sugimoto Y, Steinmetz H, Efferth T. Resistance mechanisms of cancer cells to the novel vacuolar H+-ATPase inhibitor archazolid B. Invest New Drugs. 2014;32:893–903.

    Article  CAS  PubMed  Google Scholar 

  82. Tavares-Valente D, Sousa B, Schmitt F, Baltazar F, Queirós O. Disruption of pH dynamics suppresses proliferation and potentiates doxorubicin cytotoxicity in breast cancer cells. Pharmaceutics. 2021;13(2):242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Martınez-Zaguilán R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B, et al. pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochem Pharmacol. 1999;57(9):1037–46.

    Article  PubMed  Google Scholar 

  84. Chadwick SR, Grinstein S, Freeman SA. From the inside out: ion fluxes at the centre of endocytic traffic. Curr Opin Cell Biol. 2021;71:77–86.

    Article  CAS  PubMed  Google Scholar 

  85. Martínez-Zaguilán R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B, et al. pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochem Pharmacol. 1999;57:1037.

    Article  PubMed  Google Scholar 

  86. Martin-Orozco E, Sanchez-Fernandez A, Ortiz-Parra I, Ayala-San NM. WNT signaling in tumors: the way to evade drugs and immunity. Front Immunol. 2019;10:2854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhai X, El Hiani Y. Getting lost in the cell–lysosomal entrapment of chemotherapeutics. Cancers. 2020;12(12):3669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Raghunand N, He X, Van Sluis R, Mahoney B, Baggett B, Taylor C, et al. Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer. 1999;80(7):1005–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Murakami T, Shibuya I, Ise T, Chen ZS, Si A, Nakagawa M, et al. Elevated expression of vacuolar proton pump genes and cellular PH in cisplatin resistance. Int J Cancer. 2001;93(6):869–74.

    Article  CAS  PubMed  Google Scholar 

  90. Kulshrestha A, Katara GK, Ibrahim SA, Riehl V, Sahoo M, Dolan J, et al. Targeting V-ATPase isoform restores cisplatin activity in resistant ovarian cancer: inhibition of autophagy, endosome function, and ERK/MEK pathway. J Oncol. 2019. https://doi.org/10.1155/2019/2343876.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Zalpoor H, Rezaei M, Yahyazadeh S, Ganjalikhani-Hakemi M. Flt3-ITD mutated acute myeloid leukemia patients and COVID-19: potential roles of autophagy and HIF-1α in leukemia progression and mortality. Hum Cell. 2022;35(4):1304–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Luo G, Zhou Z, Huang C, Zhang P, Sun N, Chen W, et al. Itaconic acid induces angiogenesis and suppresses apoptosis via Nrf2/autophagy to prolong the survival of multi-territory perforator flaps. Heliyon. 2023;9(7):e17909. https://doi.org/10.1016/j.heliyon.2023.e17909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yan J, Liu D, Wang J, You W, Yang W, Yan S, et al. Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance. Drug Resist Updates. 2023. https://doi.org/10.1016/j.drup.2023.101037.

    Article  Google Scholar 

  94. Akbari A, Noorbakhsh Varnosfaderani SM, Haeri MS, Fathi Z, Aziziyan F, Yousefi Rad A, et al. Autophagy induced by Helicobacter Pylori infection can lead to gastric cancer dormancy, metastasis, and recurrence: new insights. Hum Cell. 2023;37:139.

    Article  PubMed  Google Scholar 

  95. Zalpoor H, Bakhtiyari M, Akbari A, Aziziyan F, Shapourian H, Liaghat M, et al. Potential role of autophagy induced by FLT3-ITD and acid ceramidase in acute myeloid leukemia chemo-resistance: new insights. Cell Communication and Signaling. 2022;20(1):172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Li F, Li D, Liu H, Cao B-B, Jiang F, Chen D-N, et al. RNF216 regulates the migration of immortalized GnRH neurons by suppressing Beclin1-mediated autophagy. Front Endocrinol. 2019;10:12. https://doi.org/10.3389/fendo.2019.00012

    Article  Google Scholar 

  97. Dai Z, Zhu B, Yu H, Jian X, Peng J, Fang C, et al. Role of autophagy induced by arecoline in angiogenesis of oral submucous fibrosis. Arch Oral Biol. 2019;102:7–15.

    Article  CAS  PubMed  Google Scholar 

  98. Pangarkar M, Wagh U, Pathak A. Autophagy indicators in oral squamous cell carcinoma. Pathology. 2023;56:59.

    Article  PubMed  Google Scholar 

  99. Kulkarni B, Gondaliya P, Kirave P, Rawal R, Jain A, Garg R, et al. Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2. Oncotarget. 2020;11(20):1832.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Naik PP, Mukhopadhyay S, Panda PK, Sinha N, Das CK, Mishra R, et al. Autophagy regulates cisplatin-induced stemness and chemoresistance via the upregulation of CD 44, ABCB 1 and ADAM 17 in oral squamous cell carcinoma. Cell Prolif. 2018;51(1): e12411.

    Article  PubMed  Google Scholar 

  101. Li J-M, Li X, Chan LW, Hu R, Zheng T, Li H, et al. Lipotoxicity-polarised macrophage-derived exosomes regulate mitochondrial fitness through Miro1-mediated mitophagy inhibition and contribute to type 2 diabetes development in mice. Diabetologia. 2023;66(12):2368–2386.

    Article  CAS  PubMed  Google Scholar 

  102. Sambandam Y, Ethiraj P, Hathaway-Schrader JD, Novince CM, Panneerselvam E, Sundaram K, et al. Autoregulation of RANK ligand in oral squamous cell carcinoma tumor cells. J Cell Physiol. 2018;233(8):6125–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang X, Junior CR, Liu M, Li F, D’Silva NJ, Kirkwood KL. Oral squamous carcinoma cells secrete RANKL directly supporting osteolytic bone loss. Oral Oncol. 2013;49(2):119–28.

    Article  CAS  PubMed  Google Scholar 

  104. Peña-Oyarzún D, Reyes M, Hernández-Cáceres MP, Kretschmar C, Morselli E, Ramirez-Sarmiento CA, et al. Role of autophagy in the microenvironment of oral squamous cell carcinoma. Front Oncol. 2020;10: 602661.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ethiraj P, Sambandam Y, Hathaway-Schrader JD, Haque A, Novince CM, Reddy SV. RANKL triggers resistance to TRAIL-induced cell death in oral squamous cell carcinoma. J Cell Physiol. 2020;235(2):1663–73.

    Article  CAS  PubMed  Google Scholar 

  106. Zhao W, Chen C, Zhou J, Chen X, Cai K, Shen M, et al. Inhibition of autophagy promotes the anti-tumor effect of metformin in oral squamous cell carcinoma. Cancers. 2022;14(17):4185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Torigoe T, Izumi H, Ise T, Murakami T, Uramoto H, Ishiguchi H, et al. Vacuolar H+-ATPase: functional mechanisms and potential as a target for cancer chemotherapy. Anticancer Drugs. 2002;13(3):237–43.

    Article  CAS  PubMed  Google Scholar 

  108. Willingham MC, Cornwell MM, Cardarelli CO, Gottesman MM, Pastan I. Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and-sensitive KB cells: effects of verapamil and other drugs. Can Res. 1986;46(11):5941–6.

    CAS  Google Scholar 

  109. Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, et al. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Can Res. 2001;61(2):439–44.

    CAS  Google Scholar 

  110. Sasazawa Y, Futamura Y, Tashiro E, Imoto M. Vacuolar H+-ATPase inhibitors overcome Bcl-xL-mediated chemoresistance through restoration of a caspase-independent apoptotic pathway. Cancer Sci. 2009;100(8):1460–7.

    Article  CAS  PubMed  Google Scholar 

  111. Schempp CM, von Schwarzenberg K, Schreiner L, Kubisch R, Müller R, Wagner E, et al. V-ATPase inhibition regulates anoikis resistance and metastasis of cancer cells. Mol Cancer Ther. 2014;13(4):926–37.

    Article  CAS  PubMed  Google Scholar 

  112. Perut F, Avnet S, Fotia C, Baglìo SR, Salerno M, Hosogi S, et al. V-ATPase as an effective therapeutic target for sarcomas. Exp Cell Res. 2014;320(1):21–32.

    Article  CAS  PubMed  Google Scholar 

  113. Kataoka T, Muroi M, Ohkuma S, Waritani T, Magae J, Takatsuki A, et al. Prodigiosin 25-C uncouples vacuolar type H+-ATPase, inhibits vacuolar acidification and affects glycoprotein processing. FEBS Lett. 1995;359(1):53–9.

    Article  CAS  PubMed  Google Scholar 

  114. Bowman BJ, Bowman EJ. Mutations in subunit C of the vacuolar ATPase confer resistance to bafilomycin and identify a conserved antibiotic binding site. J Biol Chem. 2002;277(6):3965–72.

    Article  CAS  PubMed  Google Scholar 

  115. Boyd MR, Farina C, Belfiore P, Gagliardi S, Kim JW, Hayakawa Y, et al. Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar-type (H+)-atpases. J Pharmacol Exp Ther. 2001;297(1):114–20.

    CAS  PubMed  Google Scholar 

  116. Bowman EJ, Bowman BJ. V-ATPases as drug targets. J Bioenerg Biomembr. 2005;37:431–5.

    Article  CAS  PubMed  Google Scholar 

  117. Huss M, Sasse F, Kunze B, Jansen R, Steinmetz H, Ingenhorst G, et al. Archazolid and apicularen: novel specific V-ATPase inhibitors. BMC Biochem. 2005;6(1):1–10.

    Article  Google Scholar 

  118. Fernandes F, Loura L, Fedorov A, Dixon N, Kee T, Prieto M, et al. Binding assays of inhibitors towards selected V-ATPase domains. Biochim Biophys Acta. 2006;1758(11):1777–86.

    Article  CAS  PubMed  Google Scholar 

  119. Li S, Wu Y, Ding Y, Yu M, Ai Z. CerS6 regulates cisplatin resistance in oral squamous cell carcinoma by altering mitochondrial fission and autophagy. J Cell Physiol. 2018;233(12):9416–25.

    Article  CAS  PubMed  Google Scholar 

  120. Wang X, Liu W, Wang P, Li S. RNA interference of long noncoding RNA HOTAIR suppresses autophagy and promotes apoptosis and sensitivity to cisplatin in oral squamous cell carcinoma. J Oral Pathol Med. 2018;47(10):930–7.

    Article  CAS  PubMed  Google Scholar 

  121. Von Schwarzenberg K, Wiedmann RM, Oak P, Schulz S, Zischka H, Wanner G, et al. Mode of cell death induction by pharmacological vacuolar H+-ATPase (V-ATPase) inhibition. J Biol Chem. 2013;288(2):1385–96.

    Article  Google Scholar 

  122. Whitton B, Okamoto H, Packham G, Crabb SJ. Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer. Cancer Med. 2018;7(8):3800–11.

    Article  PubMed  PubMed Central  Google Scholar 

  123. McGuire C, Cotter K, Stransky L, Forgac M. Regulation of V-ATPase assembly and function of V-ATPases in tumor cell invasiveness. Biochim Biophys Acta. 2016;1857(8):1213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mauvezin C, Nagy P, Juhász G, Neufeld TP. Autophagosome–lysosome fusion is independent of V-ATPase-mediated acidification. Nat Commun. 2015;6(1):7007.

    Article  PubMed  Google Scholar 

  125. Guo H, Chitiprolu M, Roncevic L, Javalet C, Hemming FJ, Trung MT, et al. Atg5 disassociates the V1V0-ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy. Dev Cell. 2017;43(6):716.

    Article  CAS  PubMed  Google Scholar 

  126. Yao X, Chen H, Xu B, Lu J, Gu J, Chen F, et al. The ATPase subunit of ATP6V1C1 inhibits autophagy and enhances radiotherapy resistance in esophageal squamous cell carcinoma. Gene. 2021;768: 145261.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate Hamidreza Zalpoor (ORCID: 0000-0002-8057-2804; Email: Hamidreza.zlpr1998@gmail.com) and Ali Norouzi (ali.nowruzy7@gmail.com) for their guidance and advices, which significantly helped to improve this study.

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No fund is applicable for this study.

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Authors and Affiliations

  1. Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran

    Ahmadreza Lagzian

  2. Department of Immunology, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran

    Marziye Askari

  3. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Melika Sadat Haeri

  4. Biotechnology Department, Biological Sciences Faculty, Alzahra University, Tehran, Iran

    Nastaran Sheikhi

  5. Department of Bioscience, School of Science and Technology, Nottingham Trend University, Nottingham, UK

    Sara Banihashemi

  6. Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

    Mohsen Nabi-Afjadi

  7. Department of Microbiology, Saveh University of Medical Sciences, Saveh, Iran

    Yalda Malekzadegan

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  1. Ahmadreza Lagzian
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  2. Marziye Askari
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  7. Yalda Malekzadegan
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Contributions

A.L and M.N-A conceived the hypothesis and designed the study. A.L, M.A, MS.h, M.N-A, S.B, Y.M, and N.Sh, searched and wrote the manuscript text. M.A and S.B created the figures. M.N-A, S.B, and Y.M revised the manuscript. M.N-A and Y.M supervised the study. All authors read and approved the final manuscript.

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Correspondence to Mohsen Nabi-Afjadi or Yalda Malekzadegan.

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Lagzian, A., Askari, M., Haeri, M.S. et al. Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights. Med Oncol 41, 108 (2024). https://doi.org/10.1007/s12032-024-02313-9

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