Colorectal cancer (CRC) has emerged as the third most prevalent and second deadliest cancer worldwide. Metabolic reprogramming is a key hallmark of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) is over-expressed in multiple cancers, including CRC. Although the role of PHGDH in metabolism has been extensively investigated, its effects on CRC development remains to be elucidated. In the present study, it was demonstrated that PHGDH expression was significantly up-regulated in colorectal cancer. PHGDH expression was positively correlated with that of the aryl hydrocarbon receptor (AhR) and its target genes, CYP1A1 and CYP1B1, in CRC cells. Knockdown of PHGDH reduced AhR levels and activity, as well as the ratio of reduced to oxidized glutathione. The selective AhR antagonist stemregenin 1 induced cell death through reactive oxygen species-dependent autophagy in CRC cells. PHGDH knockdown induced CRC cell sensitivity to stemregenin 1 via the autophagy pathway. Our findings suggest that PHGDH modulates AhR signaling and the redox-dependent autophagy pathway in CRC, and that the combination of inhibition of both PHGDH and AhR may be a novel therapeutic strategy for CRC.

中文翻译：

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PHGDH 敲低通过激活自噬途径增加结直肠癌对 SR1（一种芳基碳氢化合物受体拮抗剂）的敏感性

结直肠癌 (CRC) 已成为全球第三大流行癌症和第二大致命癌症。代谢重编程是癌细胞的一个关键标志。磷酸甘油酸脱氢酶 ( PHGDH ) 在多种癌症中过度表达，包括结直肠癌。尽管 PHGDH 在代谢中的作用已被广泛研究，但其对 CRC 发展的影响仍有待阐明。在本研究中，结直肠癌中PHGDH的表达显着上调。CRC细胞中PHGDH的表达与芳烃受体（AhR）及其靶基因CYP1A1和CYP1B1的表达呈正相关。 PHGDH的敲低降低了 AhR 水平和活性，以及​​还原型谷胱甘肽与氧化型谷胱甘肽的比率。选择性 AhR 拮抗剂干细胞再生素 1 通过活性氧依赖性自噬诱导 CRC 细胞死亡。PHGDH敲低通过自噬途径诱导 CRC 细胞对干细胞再生素 1 的敏感性。我们的研究结果表明，PHGDH 调节 CRC 中的 AhR 信号传导和氧化还原依赖性自噬途径，并且联合抑制 PHGDH 和 AhR 可能是 CRC 的一种新型治疗策略。