V-ATPase at the cell surface in highly metastatic Prostate Cancer cells
Bermudez, Luis E.
Prostatic adenocarcinoma is the second-leading cause of cancer death of men in the United States. According to the American Cancer Society, there are almost 218,000 new cases and 32,000 deaths every year due to prostate cancer. The major threat comes from progression of this cancer towards metastasis. The molecular mechanisms underlying the promotion of metastasis are unclear. Metastatic tumors are highly glycolytic in nature and they tend to undergo anaerobic metabolism. This leads to the production of lactic acid that could result in intracellular acidosis. To survive in this environment, cells regulate their pH by expressing several transporters. In this study we show that metastatic prostate cancer cells use a vital transport system that counteracts intracellular acidosis and promotes metastasis, i.e. plasma membrane Vacuolar H+-ATPases (pm-V-ATPases). V-ATPases are typically found in intracellular acidic compartments. We have previously shown that V-ATPases at the cell surface are involved in breast cancer metastasis, invasiveness, and drug resistance. In this study, we demonstrated that V-ATPases are localized at the cell surface in highly metastatic prostate cancer cells using immunocytochemistry. We also demonstrated that the mRNA levels of specific subunit isoforms of V-ATPase that targets the V-ATPase to the cell surface are increased in highly metastatic prostate cancer cells when compared to non-metastatic. We monitored the activity of V-ATPases in living cells by measuring proton fluxes and specific activity in isolated membrane fractions. We also demonstrated that inhibiting the V-ATPase enhances chemosensitivity in metastatic prostate cancer cells. These data indicate that V-ATPases at the cell surface are present in highly but not in poorly metastatic cells. This suggests that the V-ATPase is a novel molecular target to enhance the efficacy of chemotherapeutic drugs to alleviate the consequences of prostate cancer metastasis.