PGC1 promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis
PGC1 promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis
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PGC1通过上调线粒体生物发生促进人卵巢癌细胞的顺铂耐药性
DOI：
10.3892/ijo.2018.4401
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发表时间：
2018-07-01
影响因子：
5.2
通讯作者：
Sun, Liankun
中科院分区：
文献类型：
--
作者：
Shen, Luyan;Sun, Boyang;Sun, Liankun
顺铂诱导细胞核和线粒体DNA损伤只是其细胞抑制/细胞毒性活性的一小部分。细胞核和细胞质中的信号通路网络可能有助于化疗耐药性。过氧化物酶体增殖物激活受体辅激活因子1（PGC 1）介导的线粒体生物合成调节线粒体结构和功能对化疗应激的适应性反应，并且可能是治疗靶点。然而，这种调控网络是复杂的，取决于肿瘤类型和环境，这需要进一步研究。我们前期的研究发现顺铂耐药的卵巢上皮癌更依赖于线粒体有氧氧化来支持其生长，提示线粒体功能与化疗耐药之间存在关联。在本研究中，它被证明，PGC 1的表达和线粒体生物合成水平在顺铂耐药SKOV 3/DDP细胞与顺铂敏感SKOV 3细胞相比，更高。此外，SKOV 3/DDP细胞上调PGC 1的表达，并通过线粒体生物合成维持线粒体结构和功能的完整性。利用短发夹RNA抑制PGC 1的表达导致SKOV 3/DDP细胞中线粒体生物合成的下调和高水平的凋亡，并且PGC 1缺陷的SKOV 3/DDP细胞中的顺铂抗性被逆转。总的来说，本研究提供的证据表明，顺铂刺激PGC 1的表达和通过PGC 1的线粒体生物合成的上调，促进细胞活力和抑制细胞凋亡，以响应顺铂治疗，从而触发卵巢癌细胞的顺铂耐药。
The induction of lesions in nuclear and mitochondrial DNA by cisplatin is only a small component of its cytostatic/cytotoxic activity. The signaling pathway network in the nucleus and cytoplasm may contribute to chemotherapeutic resistance. Peroxisome proliferator-activated receptor-coactivator 1 (PGC1)-mediated mitochondrial biogenesis regulates mitochondrial structural and the functional adaptive response against chemotherapeutic stress, and may be a therapeutic target. However, this regulatory network is complex and depends upon tumor types and environments, which require further investigation. Our previous study found that cisplatin-resistant ovarian epithelial carcinoma was more dependent on mitochondrial aerobic oxidation to support their growth, suggesting the association between mitochondrial function and chemotherapeutic resistance. In the present study, it was demonstrated that the expression of PGC1 and level of mitochondrial biogenesis were higher in cisplatin-resistant SKOV3/DDP cells compared with cisplatin-sensitive SKOV3 cells. Furthermore, SKOV3/DDP cells upregulated the expression of PGC1 and maintained mitochondrial structural and functional integrity through mitochondrial biogenesis under cisplatin stress. Inhibiting the expression of PGC1 using short hairpin RNA led to the downregulation of mitochondrial biogenesis and high levels of apoptosis in the SKOV3/DDP cells, and cisplatin resistance was reversed in the PGC1-deficient SKOV3/DDP cells. Collectively, the present study provided evidence that cisplatin stimulated the expression of PGC1 and the upregulation of mitochondrial biogenesis through PGC1, promoting cell viability and inhibiting apoptosis in response to cisplatin treatment, thus triggering cisplatin resistance in ovarian cancer cells.