Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway.
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.
Luo
Wenjing
W
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Liu
Jinyi
J
Li
Jingxia
J
Zhang
Dongyun
D
Liu
Mingchao
M
Addo
James K
JK
Patil
Shivaputra
S
Zhang
Lin
L
Yu
Jian
J
Buolamwini
John K
JK
Chen
Jingyuan
J
Huang
Chuanshu
C
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*
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