Apoptotic Cell Death by Pectenotoxin-2 in p53-Deficient Human Hepatocellular Carcinoma Cells

종양억제유전자 p53 결손 인체간암세포에서 Pectenotoxin-2에 의한 Apoptosis 유도

  • Shin, Dong-Yeok (Department of Biochemistry, Dongeui University College of Oriental Medicine) ;
  • Kim, Gi-Young (Faculty of Applied Marine Science, Cheju National Univeristy) ;
  • Choi, Byung-Tae (Department of Anatomy, School of Oriental Medicine, Pusan National University) ;
  • Kang, Ho-Sung (Department of Molecular Biology, Pusan National University) ;
  • Jung, Jee-H. (Department of Pharmacy, Pusan National University) ;
  • Choi, Yung-Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine)
  • 신동역 (동의대학교 한의과대학 생화학교실) ;
  • 김기영 (제주대학교 해양과학대학 해양과학부) ;
  • 최병태 (부산대학교 한의학전문대학원 해부학교실) ;
  • 강호성 (부산대학교 자연과학대학 분자생물학과) ;
  • 정지형 (부산대학교 약학대학 약학과) ;
  • 최영현 (동의대학교 한의과대학 생화학교실)
  • Published : 2007.10.30


Through the screening of marine natural compounds that inhibit cancer cell proliferation, we previously reported that pectenotoxin-2 (PTX-2) isolated from marine sponges exhibits selective cytotoxicity against several cell lines in p53-deficient tumor cells compared to those with functional p53. However, the molecular mechanisms of its anti-proliferative action on malignant cell growth are not completely known. To further explore the mechanisms of its anti-cancer activity and to test whether the status of p53 in liver cancer cells correlates with their chemo-sensitivities to PTX-2, we used two well-known hepatocarcinoma cell lines, p53-deficient Hep3B and p53-wild type HepG2. We have demonstrated that PTX-2 markedly inhibits Hep3B cell growth and induces apoptosis whereas HepG2 cells are much more resistant to PTX-2 suggesting that PTX-2 seems to act by p53-independent cytotoxic mechanism. The apoptosis induced by PTX-2 in Hep3B cells was associated with the modulation of DNA fragmentation factor (DFF) family proteins, up-regulation of pro-apoptotic Bcl-2 family members such as Bax and Bcl-xS and activation of caspases (caspase-3, -8 and -9). Blockade of the caspase-3 activity by caspase-3 inhibitor, z-DEVD-fmk, prevented the PTX-2-induced growth inhibition in Hep3B cells. Moreover, treatment with PTX-2 also induced phosphorylation of AKT and extracellular-signal regulating kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MARK). Specific inhibitors of PI3K inhibitor (LY294002) and ERK1/2 inhibitor (PD98059) significantly blocks PTX-2-induced-anti-proliferative effects, whereas a JNK inhibitor (SP600125) and a p38 MAPK inhibitor (SB203580) have no significant effects demonstrating that the pro-apoptotic effect of PTX-2 mediated through activation of AKT and ERK signal pathway in Hep3B cells.


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