Title: Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway.
Authors: Luo, Wenjing; Liu, Jinyi; Li, Jingxia; Zhang, Dongyun; Liu, Mingchao; Addo, James K; Patil, Shivaputra; Zhang, Lin; Yu, Jian; Buolamwini, John K; Chen, Jingyuan; Huang, Chuanshu
Published In J Biol Chem, (2008 Mar 28)
Abstract: p53, one of the most commonly mutated genes in human cancers, is thought to be associated with cancer development. Hence, screening and identifying natural or synthetic compounds with anti-cancer activity via p53-independent pathway is one of the most challenging tasks for scientists in this field. Compound JKA97 (methoxy-1-styryl-9H-pyrid-[3,4-b]-indole) is a small molecule synthetic anti-cancer agent, with unknown mechanism(s). In this study we have demonstrated that the anti-cancer activity of JKA97 is associated with apoptotic induction via p53-independent mechanisms. We found that co-incubation of human colon cancer HCT116 cells with JKA97 inhibited HCT116 cell anchorage-independent growth in vitro and tumorigenicity in nude mice and also induced a cell apoptotic response, both in the cell culture model and in a tumorigenesis nude mouse model. Further studies showed that JKA97-induced apoptosis was dramatically impaired in Bax knock-out (Bax(-/-)) HCT116 cells, whereas the knock-out of p53 or PUMA did not show any inhibitory effects. The p53-independent apoptotic induction by JKA97 was confirmed in other colon cancer and hepatocarcinoma cell lines. In addition, our results showed an induction of Bax translocation and cytochrome c release from the mitochondria to the cytosol in HCT116 cells, demonstrating that the compound induces apoptosis through a Bax-initiated mitochondria-dependent pathway. These studies provide a molecular basis for the therapeutic application of JKA97 against human cancers with p53 mutations.
PubMed ID: 18218619
MeSH Terms: Animals; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/metabolism; Apoptosis/drug effects*; Body Weight/drug effects; Carbolines/chemistry; Carbolines/pharmacology*; Cell Line, Tumor; Female; Humans; Mice; Mice, Nude; Molecular Structure; Neoplasms/genetics; Neoplasms/metabolism*; Neoplasms/pathology*; Protein Transport; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Styrenes/chemistry; Styrenes/pharmacology*; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; Xenograft Model Antitumor Assays; bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism*