title: Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway.
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.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
authors.forename: Jinyi
authors.initials: J
authors.lastname: Liu
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Mingchao
authors.initials: M
authors.lastname: Liu
authors.forename: James K
authors.initials: JK
authors.lastname: Addo
authors.forename: Shivaputra
authors.initials: S
authors.lastname: Patil
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Chen
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013343:Styrenes / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C528869:1-styryl-9H-pyrido(3,4-b)indole; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D002243:Carbolines; D011518:Proto-Oncogene Proteins; D013343:Styrenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein