Abstract
Prostate cancer (PCa) is a serious disease that affects men’s health. To date, no effective and long-lasting treatment option for this condition is available in clinical practice. ANT2 is highly expressed in a variety of hormone-related cancers, but its relationship and regulatory mechanism with PCa are unclear. In this study, we found that ANT2 expression was significantly upregulated in PCa tissues relative to control samples. Genetic knockdown of ANT2 effectively inhibited, while overexpression promoted, proliferation, migration, and invasion of PCa cells. In addition, miR-137 expression was reduced in prostate cancer tissues relative to control tissues. We identified a regulatory site for miR-137 in the 3′-UTR of ANT2 mRNA; luciferase reporter assays indicated that ANT2 is a direct target gene for miR-137. Transfecting cells with miR-137 mimics and/or an ANT2-encoding plasmid revealed that ANT2 promotes proliferation, migration, and invasion of PCa, whereas co-expression of miR-137 mimics inhibited these behaviors. These observations suggest that miR-137 mimics inhibit development of PCa by antagonizing expression of ANT2. Furthermore, tumorigenic assays in nude mice showed that miR-137 inhibitors abolished the inhibitory effect of ANT2 knockdown on PCa tumor growth. Collectively, our findings suggest that ANT2, a target gene of miR-137, is intimately involved in development of PCa, providing new evidence for the mechanism underlying pathogenesis of PCa as well as new options for targeted therapy.
Highlights
Prostate cancer (PCa) is a very common cancer in men (Bray et al, 2018), almost 20% of whom have metastatic disease at the time of diagnosis (Wu et al, 2014)
The results of qPCR revealed that expression of Adenine nucleotide translocase-2 (ANT2) mRNA was 4-fold higher in PCa tissues than in normal prostate tissues (Figure 1E), and western blotting revealed that expression of ANT2 protein was 2.8-fold higher in cancer tissues than in normal controls (Figure 1F)
High expression of ANT2, a key factor involved in maintaining mitochondrial membrane potential and preventing apoptosis, enables tumor cells to survive in a hypoxic environment and improves the anti-apoptotic ability of cancer cells
Summary
Prostate cancer (PCa) is a very common cancer in men (Bray et al, 2018), almost 20% of whom have metastatic disease at the time of diagnosis (Wu et al, 2014). Adenine nucleotide translocase-2 (ANT2) is expressed abundantly in mitochondria, and is closely associated with cell growth and proliferation (Battini et al, 1987; Barath et al, 1999). ANT2 is involved in maintaining miR-137/ANT2 Regulates Prostate Cancer the mitochondrial transmembrane potential ( ψM); it prevents mitochondrial membrane rupture to decrease the release of reactive oxygen species, inhibits mitochondrial apoptosis, and promotes tumor cell growth and resistance to chemotherapy (Dorner et al, 1997; Chevrollier et al, 2005). Silencing ANT2 effectively suppresses multiple types of tumors (Lu et al, 2017; Lee et al, 2019), and ANT2 phosphorylation inhibits apoptosis in PCa cells (Li et al, 2020). ANT2 is associated with PCa, the mechanism underlying its transcriptional regulation remains to be elucidated
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