Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Alterations in mitochondrial metabolism are considered defining characteristics and therapeutic targets of OC. Olaparib, an oral inhibitor of poly (ADP-ribose) polymerase, has been approved for the treatment of OC. However, the precise mechanisms by which it exerts its effects remain unclear. In this study, we uncover a novel pharmacological function of Olaparib by demonstrating that it induces mitochondrial dysfunction in human SKOV3 ovarian cancer cells. Our findings revealed that Olaparib exposure induced mitochondrial oxidative stress by elevating mitochondrial ROS levels and diminishing GPx activity. Additionally, treatment with Olaparib led to mitochondrial dysfunction, as evidenced by decreased complex I and complex IV activity and reduced ATP production. We observed that Olaparib induced mitochondrial fission by decreasing the average length of mitochondria. Olaparib did not affect the levels of Mfn1, Mfn2, or the total expression of Drp-1. Intriguingly, Olaparib increased the levels of phosphorylated Drp-1 at Ser616. Further investigation revealed that Olaparib facilitated the activation of the CDK5 signaling pathway and induced Caspase 3 activation. Notably, inhibition of CDK5 signaling using roscovitine mitigated the effects of Olaparib on mitochondrial fission and dysfunction, indicating a role for CDK5 in this process. In summary, our research identifies that CDK5/Drp-1-mediated mitochondrial fission may represent a novel mechanism through which Olaparib exerts its anticancer effects in OC.