Peroxisome Proliferator-Activated Receptor-γ Contributes to the Inhibitory Effects of Embelin on Colon Carcinogenesis

被引:76
作者
Dai, Yun [1 ,4 ]
Qiao, Liang [1 ]
Chan, Kwok Wah [2 ]
Yang, Mo [3 ]
Ye, Jieyu [3 ]
Ma, Juan [1 ]
Zou, Bing [1 ]
Gu, Qing [1 ]
Wang, Jide [1 ]
Pang, Roberta [1 ]
Lan, H. Y. [1 ]
Wong, Benjamin C. Y. [1 ]
机构
[1] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
[3] Univ Hong Kong, Dept Pediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China
[4] Peking Univ, Hosp 1, Dept Gastroenterol, Beijing 100871, Peoples R China
关键词
NF-KAPPA-B; PPAR-GAMMA; HEPATOCELLULAR-CARCINOMA; APOPTOSIS PROTEIN; LINKED INHIBITOR; CANCER CELLS; XIAP; GROWTH; TROGLITAZONE; EXPRESSION;
D O I
10.1158/0008-5472.CAN-08-4754
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPAR gamma is required for embelin to exert its effect. A dominant-negative PPAR gamma was used to antagonize endogenous PPAR gamma in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-kappa B (NF-kappa B) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPAR gamma(+/+) and PPAR gamma(+/-) mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPAR gamma. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPAR gamma. PPAR gamma(+/-) mice were more susceptible to DMH-induced colon carcinogenesis than PPAR gamma(+/+) mice, and embelin significantly reduced the incidence of colon cancer in PPAR gamma(+/+) mice but not in PPAR gamma(+/-) mice. Embelin inhibited NF-kappa B activity in PPAR gamma(+/+) mice but marginally so in PPAR gamma(+/-) mice. Thus, reduced expression of PPAR gamma significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPAR gamma, indicating that PPAR gamma is a necessary signaling pathway involved in the antitumor activity of norma organisms. [Cancer Res 2009;69(11):4776-83]
引用
收藏
页码:4776 / 4783
页数:8
相关论文
共 36 条
[1]
Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-κB (NF-κB) signaling pathway leading to suppression of NF-κB-regulated antiapoptotic and metastatic gene products [J].
Ahn, Kwang Seok ;
Sethi, Gautam ;
Aggarwal, Bharat B. .
MOLECULAR PHARMACOLOGY, 2007, 71 (01) :209-219
[2]
NF-κB and apoptosis in colorectal tumourigenesis [J].
Aranha, M. M. ;
Borralho, P. M. ;
Ravasco, P. ;
da Silva, I. B. Moreira ;
Correia, L. ;
Fernandes, A. ;
Camilo, M. E. ;
Rodrigues, C. M. P. .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2007, 37 (05) :416-424
[3]
c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression [J].
Baudino, TA ;
McKay, C ;
Pendeville-Samain, H ;
Nilsson, JA ;
Maclean, KH ;
White, EL ;
Davis, AC ;
Ihle, JN ;
Cleveland, JL .
GENES & DEVELOPMENT, 2002, 16 (19) :2530-2543
[4]
Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention [J].
Bertl, E ;
Bartsch, H ;
Gerhäuser, C .
MOLECULAR CANCER THERAPEUTICS, 2006, 5 (03) :575-585
[5]
Activation of PPARγ leads to inhibition of anchorage-independent growth of human colorectal cancer cells [J].
Brockman, JA ;
Gupta, RA ;
DuBois, RN .
GASTROENTEROLOGY, 1998, 115 (05) :1049-1055
[6]
Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells [J].
Carter, BZ ;
Gronda, M ;
Wang, ZL ;
Welsh, K ;
Pinilla, C ;
Andreeff, M ;
Schober, WD ;
Nefzi, A ;
Pond, GR ;
Mawji, IA ;
Houghten, RA ;
Ostresh, J ;
Brandwein, J ;
Minden, MD ;
Schuh, AC ;
Wells, RA ;
Messner, H ;
Chun, K ;
Reed, JC ;
Schimmer, AD .
BLOOD, 2005, 105 (10) :4043-4050
[7]
X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells [J].
Cummins, JM ;
Kohli, M ;
Rago, C ;
Kinzler, KW ;
Vogelstein, B ;
Bunz, F .
CANCER RESEARCH, 2004, 64 (09) :3006-3008
[8]
Loss of XIAP sensitizes rosiglitazone-induced growth inhibition of colon cancer in vivo [J].
Dai, Yun ;
Qiao, Liang ;
Chan, Kwok Wah ;
Zou, Bing ;
Ma, Juan ;
Lan, Hui Y. ;
Gu, Qing ;
Li, Zesong ;
Wang, Yan ;
Wong, Benny L. W. ;
Wong, Benjamin C. Y. .
INTERNATIONAL JOURNAL OF CANCER, 2008, 122 (12) :2858-2863
[9]
Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-κB activation and oxidative stress [J].
Derdák, Z ;
Fülöp, P ;
Sabo, E ;
Tavares, R ;
Berthiaume, EP ;
Resnick, MB ;
Paragh, G ;
Wands, JR ;
Baffy, G .
CARCINOGENESIS, 2006, 27 (05) :956-961
[10]
NF-kB in development and progression of human cancer [J].
Dolcet, X ;
Llobet, D ;
Pallares, J ;
Matias-Guiu, X .
VIRCHOWS ARCHIV, 2005, 446 (05) :475-482