Study on molecular mechanism of Norcantharidin induces apoptosis in human prostate cancer cells

Autor: Chu-Liang Lin, 林主亮
Rok vydání: 2018
Druh dokumentu: 學位論文 ; thesis
Popis: 106
Prostate cancer (PCa) is one of the most lethal malignancies, and it is the second leading cause of cancer death in American men. However, after about few years of androgen and chemo-therapy, almost all tumors will eventually develop into drug-resistant PCa with the distant metastases and poor prognosis. Therefore, development of novel therapy from nature compound is an important topic. Norcantharidin (NCTD), it has been reported to have the anti-proliferation, apoptosis, anti-metastasis and angiogenesis properties in some human cancer cell lines. This study investigates the molecular mechanism of the antitumor effects of NCTD on human prostate cancer cells. In this study, we found that NCTD inhibited the proliferation of four human prostate cancer cell line (PC3, DU145, 22Rv1 and LNcap). DAPI stain, Annexin V/PI stain, JC-1 assay and Western blot indicated that NCTD significantly induced cell apoptosis via increasing of the chromatin condensation, mitochondria dysfunction, suppressing the Bcl-2 and Mcl-1 protein expression, and activating of cleavages of caspases-3, -6, -7, -9, and -PARP. Mechanistic investigations suggested two signaling pathway involved in NCTD induced mitochondria dependent apoptosis. (1) NCTD induced FOXO4 increasment of nuclear translocation and interaction with the Mcl-1 promoter through AKT-dependent pathway, resulting in an apoptotic effect. In vivo animal model also revealed that NCTD significantly reduced tumor growth in mice with PC3 tumor xenografts. (2) Induction of miR-320d by NCTD promoted mitochondria-dependent apoptosis by targeting Mcl-1. Thus, our results provide new insights into the critical role of NCTD in PCa, which is a promising candidate of further anticancer agents for the treatment of Pca.
Databáze: Networked Digital Library of Theses & Dissertations
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