Inhibiting Mitophagy as a Novel Mechanism to Kill Prostate Cancer Cells
Abstract
The research proposed to examine the ability of inhibition of mitophagy, the mitochondrial-specific form of autophagy, to kill prostate cancer cells. Cancer cells become increasingly dependent on mitophagy as an energy source and the mitochondria themselves become more and more dysfunctional. Therefore, mitophagy may represent a novel target for the prevention of prostate cancer progression. Consequently, the purpose of this research was to test whether inhibition of mitophagy can lead to the death of prostate cancer cells. Key mediators of the mitophagic process, specifically Parkin, dynamin-related protein-1 (Drp1), fission-1 (Fis1), and cyclophilin-D (CypD), were genetically disrupted by siRNA. The effects that mitophagy blockade had on mitochondrial function, ROS production and ultimately survival of several prostate cancer cell lines was then examined. We found that on the whole, inhibition of mitophagy caused a compensatory upregulation of general autophagy and that this appeared to be a direct result of increased ROS production. Depletion of CypD actually improved mitochondrial function and ROS production and was protective against chemotherapeutic-induced cell death. In contrast, Fis1 and Parkin knockdown was sufficient to sensitize LNCaP and PC3 cells to the necrotic effects of doxorubicin. Finally, we found that Drp1 knockdown was sufficient to impair mitochondrial function, induce ROS production and reduce cell proliferation. This greatly sensitized the cells to doxorubicin such that cells were essentially gone by the time we measured apoptosis and necrosis. Consequently, our results show that inhibition of CypD is NOT a valid candidate for prostate cancer treatment. However, targeting of Fis1 and Parkin may have therapeutic value as they both sensitized prostate cancer cells to the necrotic effects of doxorubicin.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA613169
Entities
People
- Christopher P. Baines
Organizations
- University of Missouri