PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

Abstract

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 1α (PGC1α)-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 PGC1α 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 PGC1α and maintained mitochondrial structural and functional integrity through mitochondrial biogenesis under cisplatin stress. Inhibiting the expression of PGC1α 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 PGC1α-deficient SKOV3/DDP cells. Collectively, the present study provided evidence that cisplatin stimulated the expression of PGC1α and the upregulation of mitochondrial biogenesis through PGC1α, promoting cell viability and inhibiting apoptosis in response to cisplatin treatment, thus triggering cisplatin resistance in ovarian cancer cells.

Fitter Mitochondria Are Associated With Radioresistance in Human Head and Neck SQD9 Cancer Cells

“…Interestingly, a high mitophagic rate has been reported to be associated with chemoresistance in several cancer cell types (Su et al, 2016;Villa et al, 2017;Yamashita et al, 2017;Naik et al, 2018), and Zheng et al (2015) further observed that mitophagy participates in hypoxia-induced radioresistance in breast cancer cell lines. There is also good evidence that a high rate of mitochondrial biogenesis, primarily depending on activation of mitochondrial transcription factor A (TFAM) and transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), participates in chemoresistance (Gabrielson et al, 2014;Wu et al, 2016;Shen et al, 2018;Hu and Guo, 2019). TFAM and PGC-1α have not yet been linked to radioresistance, but Wang et al (2017) recently showed that silencing mitochondrial single stranded DNA-binding protein (SSBP1), a protein that normally ensures mtDNA stability, decreased mtDNA copy number and sensitized H1299 human lung cancer cells to X-ray irradiation.…”

p53/PGC‑1α‑mediated mitochondrial dysfunction promotes PC3 prostate cancer cell apoptosis

“…shrna sequences targeting human PGc-1α and a non-target sequence were constructed by Genechem co., ltd. (Shanghai, china. ), as previously described (16). The sequences of PGc-1α shrna and the non-target shrna were 5'-GTT aTa ccT GTG aTG cTT T-3' and 5'-TTc Tcc Gaa cGT GTc acG T-3', respectively.…”

“…coverslips were placed in 24-well plates and 8x10 4 cells were added into each well. Mitochondria were stained in live cells using MitoTracker™ red cMXros (invitrogen; Thermo Fisher Scientific, inc.), as previously described (16).…”

Resensitization of cisplatin resistance ovarian cancer cells to cisplatin through pretreatment with low‐dose fraction radiation

“…The drug-resistant ovarian cancer cell line, SKOV3/DDP, was bought from the Institute of Cancer Research, Chinese Academy of Medical Sciences (Beijing, China). 19,20 Cell counting kit-8 (CCK-8) and Annexin V-FITC were purchased from Jiamay Biotech (The catalog numbers are AP1008 and LHK601-100, respectively; China). Primary antibodies against FOXO3a or PUMA were purchased from Abcam (The catalog numbers are ab12162 and ab9643, respectively; USA).…”