Data from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

Abstract

<div>Abstract<p>Olaparib, a PARP inhibitor, is a targeted therapy used in treating various cancers, including castration-resistant prostate cancer. Despite its efficacy, resistance to olaparib remains a significant challenge. Understanding the molecular mechanisms underpinning this resistance is crucial for developing more effective treatment strategies. This study focuses on elucidating the role of mitochondrial alterations and the PTEN-induced kinase 1 (<i>PINK1</i>) gene in conferring olaparib resistance in castration-resistant prostate cancer cells. We investigated the transcriptomic and functional differences in mitochondrial activity between olaparib-resistant (2B-OlapR, LN-OlapR) and treatment-naïve prostate cancer cells (C4-2B, LNCaP) in both castration-sensitive and -resistant settings. Through RNA sequencing and gene set enrichment analysis, we identified significant enrichment of mitochondrial activity– and oxidative phosphorylation–related gene sets in olaparib-resistant derived cell lines. Resistant lines exhibited enhanced mitochondrial functionality, including increased basal and maximal respiration rates, as well as elevated ATP production and spare respiratory capacity, compared with parental cells. Subsequent investigations revealed a substantial increase in mitochondrial mass and electron transport chain complex I activity in olaparib-resistant cells. Furthermore, overexpression of the <i>PINK1</i> gene was observed in resistant cells, which was correlated with resistance to olaparib and poor clinical outcomes in patients with prostate cancer. Inhibition of PINK1 expression significantly reduced mitochondrial function and mass, impaired cell growth, and decreased resistance to olaparib. These findings suggest that PINK1 plays a crucial role in modulating mitochondrial dynamics that confer therapeutic resistance, highlighting its potential as a therapeutic target for overcoming olaparib resistance in prostate cancer.</p>Significance:<p>Olaparib, a PARP inhibitor, is effective against various cancers, including prostate cancer. However, resistance to olaparib poses a significant challenge. This study uncovers that mitochondrial alterations and <i>PINK1</i> gene overexpression contribute to this resistance in prostate cancer cells. Enhanced mitochondrial functionality and increased PINK1 expression in olaparib-resistant cells underscore the importance of targeting mitochondrial dynamics and PINK1 to develop more effective treatments for overcoming olaparib resistance in prostate cancer.</p></div>