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Abstract：
Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
摘要：
尽管铂类化疗是结直肠癌（CRC）的一线治疗方案，耐药性仍然是影响其治疗效率的主要挑战。然而,关于化疗耐药与脂质代谢的相关性研究有限，包括PIK3CA突变肿瘤。在本研究中,我们发现PIK3CA-E545K突变可在体外和体内减轻L-OHP治疗的CRC细胞凋亡并增加细胞活力.机械上,PIK3CA-E545K突变促进SREBP1的核积累，从而促进载脂蛋白A5（APOA5）的转录。APOA5激活PPARγ信号通路以减轻L-OHP治疗后活性氧（ROS）的产生，这有助于CRC细胞的细胞存活。此外，APOA5过表达增强了CRC细胞的干性相关性状。增加的APOA5表达与肿瘤标本中的PIK3CA突变和对一线化疗的不良反应有关。这是CRC患者化疗敏感性的独立有害因素。一起来看,这项研究表明PIK3CA-E545K突变通过上调CRC中的APOA5转录来促进L-OHP抗性,这可能是提高L-OHP化疗效率的有效靶点。我们的研究揭示了通过营养管理提高CRC化疗敏感性。
