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Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells.

ABSTRACT: Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-?B) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis.

SUBMITTER: Hwang ST

PROVIDER: S-EPMC7144730 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells.

Hwang Sun Tae ST Um Jae-Young JY Chinnathambi Arunachalam A Alharbi Sulaiman Ali SA Narula Acharan S AS Namjoshi Ojas A OA Blough Bruce E BE Ahn Kwang Seok KS

Molecules (Basel, Switzerland) 20200313 6

Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted tha ...[more]

PMID: 32183146

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Project description:Simple Summary We describe the unique role of guadecitabine (gDEC) activating lysine methyltransferases (KMTs) in association with prostate cancer inhibition. This study suggests that one consequence of DNMT1-targeting by gDEC is the upregulation of epigenetic activating enzymes to contribute to the overall prostate cancer phenotype change and anticancer effect independent of apoptosis. Mechanistically, gDEC increases the mono- and di-methylation of H3K4 in prostate cancer cell lines and was associated with DNMT1 depletion. Importantly, DNMT1-targeting with gDEC to reverse aberrant epigenetic repression of tumor suppressor programs suggests the therapeutic potential of treating prostate cancer. Abstract Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and β-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.

Dataset Information

Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells.

Publications

Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells.

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