Abstract
The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-β), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3–24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-β signaling, including the androgen/TGF-β inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.
Highlights
Prostate cancer is the second most frequent male cancer and a leading cause of morbidity and mortality in men worldwide [1]
We extended our knowledge to localize new gene signatures and signaling pathways responding to curcumin treatment in prostate cancer cells to further elucidate the anti-tumor mechanism of curcumin
It was noted that 12 h post curcumin treatment was the peak time point with maximum number of genes affected by curcumin treatment in both LNCaP (1273 genes up-regulated and 1682 genes down-regulated) and C4-2B (1119 genes up-regulated and 943 genes down-regulated) cells
Summary
Prostate cancer is the second most frequent male cancer and a leading cause of morbidity and mortality in men worldwide [1]. For prostate cancer prevention and treatment, it has been very important to dissect the underlying molecular signaling pathways contributing to cancer development and progression. Curcumin has been shown to inhibit proliferation and invasion and induce apoptosis of prostate cancer cells in vitro and in vivo through interfering with various signaling pathways including mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR), and nuclear factor κ (NFκB) [7,8,9]. Our previous study has shown that curcumin caused the decrease in expression of various AR regulated genes (NKX3.1 (NK3 Homeobox 1), KLK3/(PSA) (Kallikrein related peptidase 3/ Prostate-specific antigen), TMPRSS2 (Transmembrane serine protease 2) in a time-dependent manner in both androgen-dependent LNCaP and androgen-independent C4-2B cells [21]. It is well understood that the prostate cancer progression and bone metastasis is mediated through dysregulation of multiple cell signaling pathways, and the majority of prostate cancer drugs control specific targets
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