Insensitivity and resistance to 5-fluorouracil (5FU) remain as major hurdles for effective and durable 5FU-based chemotherapy in colorectal cancer (CRC) patients. In this study, we identified prostaglandin E synthase (PTGES)/prostaglandin E2 (PGE2) axis as an important regulator for 5FU sensitivity in CRC cells. We found that PTGES expression and PGE2 production are elevated in CRC cells in comparison to normal colorectal epithelial cells. Depletion of PTGES significantly enhanced the inhibitory effect of 5FU on CRC cell viability that was fully reverted by exogenous supplement of PGE2. Inhibition of PTGES enzymatic function, by either inducing loss-of-function mutant or treatment with selective inhibitors, phenocopied the PTGES depletion in terms of 5FU sensitization. Mechanistically, PTGES/PGE2 axis modulates glycolysis in CRC cells, thereby regulating the 5FU sensitivity. Importantly, high PTGES expression is correlated with poor prognosis in 5FU-treated CRC patients. Thus, our study defines PTGES/PGE2 axis as a novel therapeutic target for enhancing the efficacy of 5FU-based chemotherapy in CRC.

中文翻译：

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靶向 PTGES/PGE2 轴可增强结直肠癌细胞对 5-氟尿嘧啶的敏感性。

对 5-氟尿嘧啶 (5FU) 的不敏感性和耐药性仍然是结直肠癌 (CRC) 患者进行有效且持久的基于 5FU 的化疗的主要障碍。在这项研究中，我们发现前列腺素 E 合酶 (PTGES)/前列腺素 E2 (PGE2) 轴是 CRC 细胞 5FU 敏感性的重要调节因子。我们发现，与正常结直肠上皮细胞相比，CRC 细胞中 PTGES 表达和 PGE2 产量升高。PGES 的消耗显着增强了 5FU 对 CRC 细胞活力的抑制作用，而外源性补充 PGE2 可完全恢复这种抑制作用。通过诱导功能丧失突变体或用选择性抑制剂治疗来抑制 PTGES 酶功能，根据 5FU 致敏表现出 PTGES 消耗的表型。从机制上讲，PTGES/PGE2 轴调节 CRC 细胞中的糖酵解，从而调节5FU敏感性。重要的是，PTGES 高表达与 5FU 治疗的 CRC 患者预后不良相关。因此，我们的研究将 PTGES/PGE2 轴定义为增强基于 5FU 的化疗在 CRC 中的疗效的新治疗靶点。