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Transgelin induces apoptosis of human prostate LNCaP cells through its interaction with p53.

ABSTRACT: The androgen receptor (AR) and its coregulators have important roles in the carcinogenesis of prostate cancer. p53 is an important tumour suppressor gene, and the absence of a fundamental p53 response may predispose to cancer. Transgelin, known as an ARA54-associated AR inhibitor, can suppress AR function in LNCaP cells. In addition to these effects, we aimed to elucidate the proapoptotic effects of the protein on LNCaP and its underlying mechanisms, especially the interaction between transgelin and p53. Cell counting, flow cytometric analysis and terminal deoxynucleotidyl transferase-dUTP nick-end labelling assays were applied to measure the proapoptotic effect of transgelin. Using western blotting of p53 and double immunofluorescence staining of p53 with transgelin, we show that transfection of transgelin results in increasing cytoplasmic translocation of p53 and upregulation of p53 expression. We also found an interaction between transgelin and p53 in vivo by mammalian two-hybrid and coimmunoprecipitation assays. The activation of the mitochondria-associated apoptosis pathway was observed in LNCaP cells after transfection with transgelin. These results are indicative of p53-mediated mitochondria-associated apoptotic effects of transgelin on LNCaP cells in addition to its known suppressive effects on the AR pathway.

SUBMITTER: Zhang ZW

PROVIDER: S-EPMC3739090 | biostudies-other | 2010 Mar

REPOSITORIES: biostudies-other

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Project description:BackgroundDespite the advancement in chemotherapeutic drugs for colon cancer treatment, it is still a life-threatening disease worldwide due to drug resistance. Therefore, an urgently needed to develop novel drugs for colon cancer therapies. AGA is a combination of traditional Chinese medicine Antler's extract (A), Ganoderma lucidum (G), and Antrodia camphorata (A); it contains a lot of biomolecules like polysaccharides, fatty acids, and triterpenoids that are known to exerting anti-oxidative, anti-inflammatory, anti-microbial and anti-tumor activities in oral cancer. In this study, we investigate AGA anti-proliferative, anti-metastatic and apoptotic activity to explore its anti-cancer activity against colon cancer cells and its underlying mechanism.MethodHere, in-vitro studies were performed to determine the antiproliferative activity of AGA through MTT and colony formation assays. Wound healing and transwell migration assay were used to evaluate the metastasis. Flow cytometry and protein expression were used to investigate the involved molecular mechanism by evaluating the cell cycle and apoptosis. The in-vivo anti-cancerous activity of AGA was assessed by xenograft mice model of colon cancer cells.ResultsWe found that AGA significantly inhibited the proliferative capacity and metastasis of colon cancer cells in-vitro. In addition, AGA induced cell cycle arrest in the sub-G1 phase through upregulating p21 and downregulating CDK2, CDK6 in SW620, and CDK4 in SW480 and HT29, respectively. Annexin-v assay indicated that colon cancer cells had entered early and late apoptosis after treatment with AGA. Furthermore, a mechanistic protein expressions study revealed that AGA in p53-dependent and independent regulated the apoptosis of colon cancer by downregulating the p53 protein expression in SW620 and SW480 cells but upregulating in a dose-dependent manner in HT29 cells and increasing the expression of Bax and caspase-9 to inhibit the colon cancer cells. In vivo study, we found that AGA significantly reduced the xenograft tumor growth in NOD/SCID mice with no adverse effect on the kidney and liver.ConclusionCollectively, AGA has the potential to inhibit colon cancer through inhibiting proliferation, migration, and cell cycle kinase by upregulating p21 protein expression and promoting the apoptotic protein in a p53-dependent and independent manner.

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Transgelin induces apoptosis of human prostate LNCaP cells through its interaction with p53.

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