Skip to main content
SpringerLink
Log in

REEP3 as a Novel Oncogene Contributes to the Warburg Effect in Pancreatic Cancer Cells by Activating the EGFR/ERK Pathway

  • CELL MOLECULAR BIOLOGY
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Emerging evidence indicates that the Warburg effect (aerobic glycolysis) is a marker of malignancy in pancreatic cancer (PC). Receptor expression–enhancing protein 3 (REEP3) is dysregulated in various cancers; however, no studies have addressed whether REEP3 is involved in regulating PC malignancy, particularly with respect to the Warburg effect. Herein, we identified a new diagnostic marker of PC, which may be useful for developing drugs to treat PC and providing insight into the molecular pathology of PC. The microarray dataset GSE183795 was retrieved from the Gene Expression Omnibus database and the differentially expressed genes were analyzed. REEP3 expression was examined in PC cell lines and normal pancreatic ductal epithelial cells. Following REEP3 knockdown or overexpression in PC cells, cell invasion, migration, glucose uptake, lactate production, ATP levels, and epidermal growth factor receptor (EGFR)/extracellular regulated kinase (ERK) pathway protein expression were assessed via scratch, Transwell, glucose, and lactate assays and western blot analysis. A database analysis revealed that REEP3 was highly expressed in PC tumor tissues from 179 patients. In addition, patients with high REEP3 tumor expression exhibited poor overall and disease-free survival. Our results suggest that REEP3 is upregulated in multiple PC cell lines. Moreover, cell viability indicators, such as proliferation, invasion, migration, glycolytic activity, and EGFR/ERK pathway protein expression were conspicuously restrained on REEP3 disruption in PC cells. Overall, these findings suggest that REEP3 assists PC cell proliferation, invasion, and migration by facilitating the Warburg effect through the activation of the EGFR/ERK signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

REFERENCES

  1. Ansari D., Tingstedt B., Andersson B., Holmquist F., Sturesson C., Williamsson C., Sasor A., Borg D., Bauden M. Andersson R. 2016. Pancreatic cancer: Yesterday, today and tomorrow. Future Oncol. 12, 1929‒1946.

    Article  CAS  PubMed  Google Scholar 

  2. Wood L.D., Canto M.I., Jaffee E.M. Simeone D.M. 2022. Pancreatic cancer: Pathogenesis, screening, diagnosis, and treatment. Gastroenterology. 163, 386‒402.e1.

    Article  PubMed  Google Scholar 

  3. Springfeld C., Jäger D., Büchler M.W., Strobel O., Hackert T., Palmer D.H., Neoptolemos J.P. 2019. Chemotherapy for pancreatic cancer. Presse Med. 48, e159‒e174.

    Article  PubMed  Google Scholar 

  4. Vaupel P., Schmidberger H., Mayer A. 2019. The Warburg effect: Essential part of metabolic reprogramming and central contributor to cancer progression. Int. J. Radiat. Biol. 95, 912‒919.

    Article  CAS  PubMed  Google Scholar 

  5. Koppenol W.H., Bounds P.L. Dang C.V. 2011. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer. 11, 325‒337.

    Article  CAS  PubMed  Google Scholar 

  6. Liang L., Li W., Li X., Jin X., Liao Q., Li Y., Zhou Y. 2022. ‘Reverse Warburg effect’ of cancer‑associated fibroblasts (review). Int. J. Oncol. 60, 67.

    Article  CAS  PubMed  Google Scholar 

  7. Yang J., Ren B., Yang G., Wang H., Chen G., You L., Zhang T. Zhao Y. 2020. The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol. Life Sci. 77, 305‒321.

    Article  CAS  PubMed  Google Scholar 

  8. Björk S., Hurt C.M., Ho V.K., Angelotti T. 2013. REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity. PLoS One. 8, e76366.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bock F.J., Tait S.W.G. 2018. p53 REEPs to sow ER-mitochondrial contacts. Cell Res. 28, 877‒878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fan S., Liu H., Li L. 2022. The REEP family of proteins: Molecular targets and role in pathophysiology. Pharmacol. Res. 185, 106477.

    Article  CAS  PubMed  Google Scholar 

  11. Wei H., Yan S., Hui Y., Liu Y., Guo H., Li Q., Li J., Chang Z. 2020. CircFAT1 promotes hepatocellular carcinoma progression via miR-30a-5p/REEP3 pathway. J. Cell Mol. Med. 24, 14561‒14570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kolbeinsson H.M., Chandana S., Wright G.P., Chung M. 2023. Pancreatic cancer: a review of current treatment and novel therapies. J. Invest. Surg. 36, 2129884.

    Article  PubMed  Google Scholar 

  13. Wang N., Clark L.D., Gao Y., Kozlov M.M., Shemesh T., Rapoport T.A. 2021. Mechanism of membrane-curvature generation by ER-tubule shaping proteins. Nat. Commun. 12, 568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Son Y., Choi C., Saha A., Park J.H., Im H., Cho Y.K., Seong J.K., Burl R.B., Rondini E.A., Granneman J.G., Lee Y.H. 2022. REEP6 knockout leads to defective β-adrenergic signaling in adipocytes and promotes obesity-related metabolic dysfunction. Metabolism. 130, 155159.

    Article  CAS  PubMed  Google Scholar 

  15. Yao L., Xie D., Geng L., Shi D., Huang J., Wu Y., Lv F., Liang D., Li L., Liu Y., Li J., Chen Y.H. 2018. REEP5 (Receptor Accessory Protein 5) acts as a sarcoplasmic reticulum membrane sculptor to modulate cardiac function. J. Am. Heart. Assoc. 7, e007205.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Esteves T., Durr A., Mundwiller E., Loureiro J.L., Boutry M., Gonzalez M.A., Gauthier J., El-Hachimi K.H., Depienne C., Muriel M.P., Acosta Lebrigio R.F., Gaussen M., Noreau A., Speziani F., Dionne-Laporte A., Deleuze J.F., Dion P., Coutinho P., Rouleau G.A., Zuchner S., Brice A., Stevanin G., Darios F. 2014. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am. J. Hum. Genet. 94, 268‒277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hurt C.M., Björk S., Ho V.K., Gilsbach R., Hein L., Angelotti T. 2014. REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues. Brain Res. 1545, 12‒22.

    Article  CAS  PubMed  Google Scholar 

  18. Feng L., Yin Y.Y., Liu C.H., Xu K.R., Li Q.R., Wu J.R., Zeng R. 2020. Proteome-wide data analysis reveals tissue-specific network associated with SARS-CoV-2 infection. J. Mol. Cell Biol. 12, 946‒957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Voloshanenko O., Schwartz U., Kranz D., Rauscher B., Linnebacher M., Augustin I., Boutros M. 2018. β-Catenin-independent regulation of Wnt target genes by RoR2 and ATF2/ATF4 in colon cancer cells. Sci. Rep. 8, 3178.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhao C., Lou Y., Wang Y., Wang D., Tang L., Gao X., Zhang K., Xu W., Liu T., Xiao J. 2019. A gene expression signature-based nomogram model in prediction of breast cancer bone metastases. Cancer Med. 8, 200‒208.

    Article  CAS  PubMed  Google Scholar 

  21. Chang H., Rha S.Y., Jeung H.C., Jung J.J., Kim T.S., Kwon H.J., Kim B.S., Chung H.C. 2010. Identification of genes related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells. J. Cancer Res. Clin. Oncol. 136, 1901‒1913.

    Article  CAS  PubMed  Google Scholar 

  22. Park C.R., You D.J., Park S., Mander S., Jang D.E., Yeom S.C., Oh S.H., Ahn C., Lee S.H., Seong J.Y., Hwang J.I. 2016. The accessory proteins REEP5 and REEP6 refine CXCR1-mediated cellular responses and lung cancer progression. Sci. Rep. 6, 39041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fang J., Ji W.H., Wang F.Z., Xie T.M., Wang L., Fu Z.F., Wang Z., Yan F.Q., Shen Q.L., Ye Z.M. 2021. Circular RNA hsa_circ_0000700 promotes cell proliferation and migration in esophageal squamous cell carcinoma by sponging miR-1229. J. Cancer. 12, 2610‒2623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abbaszadeh Z., Çeşmeli S., Biray Avcı Ç. 2020. Crucial players in glycolysis: Cancer progress. Gene. 726, 144158.

    Article  CAS  PubMed  Google Scholar 

  25. Li Z., Zhang H. 2016. Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol. Life Sci. 73, 377‒392.

    Article  CAS  PubMed  Google Scholar 

  26. Yang R., Li X., Wu Y., Zhang G., Liu X., Li Y., Bao Y., Yang W., Cui H. 2020. EGFR activates GDH1 transcription to promote glutamine metabolism through MEK/ERK/ELK1 pathway in glioblastoma. Oncogene. 39, 2975‒2986.

    Article  CAS  PubMed  Google Scholar 

  27. Sabbah D.A., Hajjo R., Sweidan K. 2020. Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors. Curr. Top. Med. Chem. 20, 815‒834.

    Article  CAS  PubMed  Google Scholar 

  28. Chong C.R., Jänne P.A. 2013. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med. 19, 1389‒1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nicholson R.I., Gee J.M., Harper M.E. 2001. EGFR and cancer prognosis. Eur. J. Cancer. 37 (Suppl. 4), S9‒S15.

    Article  CAS  PubMed  Google Scholar 

  30. Wang G., Li Y., Yang Z., Xu W., Yang Y., Tan X. 2018. ROS mediated EGFR/MEK/ERK/HIF-1α loop regulates glucose metabolism in pancreatic cancer. Biochem. Biophys. Res. Commun. 500, 873‒878.

    Article  CAS  PubMed  Google Scholar 

  31. Bernier M., Catazaro J., Singh N.S., Wnorowski A., Boguszewska-Czubara A., Jozwiak K., Powers R., Wainer I.W. 2017. GPR55 receptor antagonist decreases glycolytic activity in PANC-1 pancreatic cancer cell line and tumor xenografts. Int. J. Cancer. 141, 2131‒2142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was sponsored by the Ningbo Science and Technology Bureau (Ningbo, no. 2022S041).

Author information

Authors and Affiliations

  1. Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Ningbo University, 315000, Ningbo, China

    A. Wang & X. P. Yang

Authors
  1. A. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. C. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X. P. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by An Wang, Yucheng Huang, and Xiaoping Yang. The first draft of the manuscript was written by An Wang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to A. Wang.

Ethics declarations

CONFLICT OF INTEREST

The authors of this work declare that they have no conflicts of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

This work does not contain any studies involving human and animal subjects.

Additional information

Publisher’s Note.

Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, A., Huang, Y.C. & Yang, X.P. REEP3 as a Novel Oncogene Contributes to the Warburg Effect in Pancreatic Cancer Cells by Activating the EGFR/ERK Pathway. Mol Biol 58, 300–310 (2024). https://doi.org/10.1134/S0026893324020171

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893324020171

Keywords:

Search

Navigation