Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 336-745, Korea.
Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 330-930, Korea.
Int J Mol Sci. 2019 Apr 5;20(7):1707. doi: 10.3390/ijms20071707.
Anti-cancer drug resistance is a serious issue for patients with colorectal cancer (CRC). Although recent studies have shown the mechanism by which CRC cells become drug resistant, novel strategies for overcoming this drug resistance have not yet been developed. To address this problem, we characterized 5-fluorouracil (5FU)-resistant CRC cells after treatment with 5FU, and focused on the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in these cells. In 5FU-resistant CRC cells, the 5FU did not considerably decrease the mitochondrial biogenesis or mitochondrial complex I and IV activities, and only partially decreased the antioxidant enzymatic activity, oxygen consumption ratio, and cell survival. The expression of PGC-1α was remarkably increased in the 5FU-resistant CRC cells compared with the 5FU-sensitive CRC cells. The 5FU-resistant CRC cells displayed enhanced mitochondrial biogenesis, oxidative phosphorylation, and antioxidant enzyme activities against 5FU-induced reactive oxygen species, because of the increased expression of PGC-1α. PGC-1α inhibited 5FU-induced endoplasmic reticulum (ER) stress in the 5FU-resistant CRC cells, resulting in the suppression of apoptosis. These findings reveal that PGC-1α plays an important role in drug resistance in 5FU-resistant CRC cells. Moreover, PGC-1α could serve as a novel target in patients with 5FU-resistant CRC.
抗癌药物耐药性是结直肠癌（CRC）患者面临的一个严重问题。尽管最近的研究表明了 CRC 细胞产生耐药性的机制，但尚未开发出克服这种耐药性的新策略。为了解决这个问题，我们对经 5-氟尿嘧啶（5FU）处理后具有耐药性的 CRC 细胞进行了特征描述，并重点研究了这些细胞中过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1α）的表达。在 5FU 耐药的 CRC 细胞中，5FU 并没有显著降低线粒体生物发生或线粒体复合物 I 和 IV 的活性，只是部分降低了抗氧化酶活性、耗氧比和细胞存活率。与 5FU 敏感的 CRC 细胞相比，5FU 耐药的 CRC 细胞中 PGC-1α 的表达显著增加。由于 PGC-1α 的表达增加，5FU 耐药的 CRC 细胞表现出增强的线粒体生物发生、氧化磷酸化和抗氧化酶活性，以应对 5FU 诱导的活性氧。PGC-1α 抑制了 5FU 耐药的 CRC 细胞中的内质网（ER）应激，从而抑制了细胞凋亡。这些发现表明 PGC-1α 在 5FU 耐药的 CRC 细胞耐药性中发挥着重要作用。此外，PGC-1α 可能成为 5FU 耐药的 CRC 患者的一个新靶点。
