PGC1α Promotes Cisplatin Resistance in Ovarian Cancer by Regulating the HSP70/HK2/VDAC1 Signaling Pathway.

Yanqing Li,Jiaying Fu,Liankun Sun,Haoge Luo,Yang Li,Yanan Liu,Jinsong Kang

doi:10.3390/ijms22052537

Abstract

Mitochondrial apoptosis is one of the main mechanisms for cancer cells to overcome chemoresistance. Hexokinase 2 (HK2) can resist cancer cell apoptosis by expressing on mitochondria and binding to voltage-dependent anion channel 1 (VDAC1). We previously reported that peroxisome proliferator-activated receptor coactivator 1 α (PGC1α) is highly expressed in ovarian cancer cisplatin-resistant cells. However, the underlying mechanism remains unclear. Therefore, we evaluated the interaction between PGC1α and HK2 in ovarian cancer cisplatin-resistant cells. We found that the knockdown of PGC1α promotes the apoptosis of ovarian cancer cisplatin-resistant cells and increases their sensitivity to cisplatin. In addition, we found that the knockdown of PGC1α affects the mitochondrial membrane potential and the binding of HK2 and VDAC1. As the heat shock protein 70 (HSP70) family can help protein transport, we detected it and found that PGC1α can promote HSP70 gene transcription. Furthermore, HSP70 can promote an increase of HK2 expression on mitochondria and an increase of binding to VDAC1. Based on these results, PGC1α may reduce apoptosis through the HSP70/HK2/VDAC1 signaling pathway, thus promoting cisplatin resistance of ovarian cancer. These findings provide strong theoretical support for PGC1α as a potential therapeutic target of cisplatin resistance in ovarian cancer.

Highlights

Cisplatin resistance is still one of the main causes of death in ovarian cancer patients [1].Cisplatin resistance can be produced through a variety of mechanisms, such as the cisplatin transport system and the mitochondrial signal pathway [2]
In this study, we explored the mitochondrial apoptosis mediated by PGC1α through the heat shock protein 70 (HSP70)/Hexokinase 2 (HK2)/voltage-dependent anion channel 1 (VDAC1) signaling pathway, which may provide a new strategy for inducing apoptosis of cisplatin-resistant cancer cells
Knockdown of PGC1α Promotes the Apoptosis of Cisplatin-Resistant Ovarian Cancer Cells

Summary

Introduction

Cisplatin resistance is still one of the main causes of death in ovarian cancer patients [1].Cisplatin resistance can be produced through a variety of mechanisms, such as the cisplatin transport system and the mitochondrial signal pathway [2]. Cisplatin resistance is still one of the main causes of death in ovarian cancer patients [1]. Mitochondria can resist chemotherapy resistance by regulating cell metabolism and apoptosis signals [3,4]. To cope with the stress caused by chemotherapeutic drugs and to survive, tumor cells use mitochondrial adaptive mechanisms such as mitochondrial biosynthesis and mitochondrial metabolism [5,6]. Studies have demonstrated that mitochondrial biosynthesis-related molecules, such as peroxisome proliferator-activated receptor coactivator 1 α (PGC1α), can regulate apoptosis signaling by interacting with mitochondrial proteins [7,8]. Targeting mitochondria is a crucial step in preventing the chemotherapy resistance of tumor cells. The specific mechanism of mitochondrial resistance to chemotherapy in cisplatin-resistant ovarian cancer cells remains unclear

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Discussion

Conclusion