Investigating the effects of the polyphenol, carnosic acid, in prostate cancer

Abstract

Prostate cancer (PCa), accounting for 375,304 deaths in 2020, is the second most prevalent cancer in men worldwide. While many treatments exist for PCa, novel therapeutic agents with higher efficacy are needed to target aggressive and hormone-resistant forms of PCa, while sparing healthy cells. Plant-derived chemotherapy drugs such as docetaxel (DTX) and paclitaxel (PTX) have been established to treat cancers including PCa. Carnosic acid (CA), a phenolic diterpene found in the herb rosemary (Rosmarinus officinalis) has been shown to have anticancer properties but its effects in PCa and its mechanisms of action have not been examined. CA dose-dependently inhibited PC- 3 and LNCaP prostate cancer cell survival and proliferation (IC50: 64, 21 μM, respectively) and stimulated a dose-dependent decrease in cell migration. CA decreased phosphorylation and activation of Akt, mTOR, and p70 S6K. A notable increase in phosphorylation of AMP-activated kinase (AMPK), phosphorylation of its downstream target acetyl-CoA carboxylase (ACC) and increased levels of the upstream regulator of AMPK, sestrin-2 was seen with CA treatment. Furthermore, there was a significant increase in the phosphorylation of apoptosis-signal-regulating kinase-1 (ASK1), and p38 MAPK and in cleaved PARP suggesting an increase in apoptosis. Our data indicate that CA inhibits AKT-mTORC1-p70S6K and activates Sestrin-2-AMPK-ASK1 signaling in PCa cells leading to a decrease in survival, proliferation and induction of apoptosis. The use of inhibitors and small RNA interference (siRNA) approaches should be employed in future studies to elucidate the mechanisms involved in these inhibitory effects of CA on PCa.