Abstract
The accumulation of neutral lipids in intracellular lipid droplets has been associated with the formation and progression of many cancers, including prostate cancer (PCa). Alpha-beta Hydrolase Domain Containing 5 (ABHD5) is a key regulator of intracellular neutral lipids that has been recently identified as a tumor suppressor in colorectal cancer, yet its potential role in PCa has not been investigated. Through mining publicly accessible PCa gene expression datasets, we found that ABHD5 gene expression is markedly decreased in metastatic castration-resistant PCa (mCRPC) samples. We further demonstrated that RNAi-mediated ABHD5 silencing promotes, whereas ectopic ABHD5 overexpression inhibits, the invasion and proliferation of PCa cells. Mechanistically, we found that ABHD5 knockdown induces epithelial to mesenchymal transition, increasing aerobic glycolysis by upregulating the glycolytic enzymes hexokinase 2 and phosphofrucokinase, while decreasing mitochondrial respiration by downregulating respiratory chain complexes I and III. Interestingly, knockdown of ATGL, the best-known molecular target of ABHD5, impeded the proliferation and invasion, suggesting an ATGL-independent role of ABHD5 in modulating PCa aggressiveness. Collectively, these results provide evidence that ABHD5 acts as a metabolic tumor suppressor in PCa that prevents EMT and the Warburg effect, and indicates that ABHD5 is a potential therapeutic target against mCRPC, the deadly aggressive PCa.
Highlights
Prostate cancer (PCa) is the most common solid organ malignancy in men and the second leading cause of cancer-related death reported in industrialized countries[1]
These results suggest that Alpha-beta Hydrolase Domain Containing 5 (ABHD5) gene expression is suppressed in metastatic and castration-resistant PCa (mCRPC)
Reprogramming of cellular metabolism has been linked to the progression of prostate tumors[30,31], raising the possibility that new therapeutic targets might be discovered in the pathways that support aberrant metabolism in prostate cancer (PCa)
Summary
Prostate cancer (PCa) is the most common solid organ malignancy in men and the second leading cause of cancer-related death reported in industrialized countries[1]. The phenomenon of aerobic glycolysis, termed the Warburg effect[6], is a central feature of cancer cell metabolism that efficiently reserves anabolic building blocks for proliferation and reduces oxidative stress resulting from mitochondrial respiration, providing proliferative and survival advantages[7,8]. Ablation of ABHD5 gene in liver decreases respiration and increases glycolysis, conferring a metabolic state reminiscent of the Warburg effect[21]. These data suggest that alteration of ABHD5 might influence cancer metabolism. Our results indicate that ABHD5 suppresses PCa aggressiveness by supporting oxidative metabolism, and suggest that activation of ABHD5 might be useful in treatment of advanced PCa
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
