Heat shock protein 27 mediates the effect of 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone on mitochondrial apoptosis in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a global public health problem which causes approximately 500,000 deaths annually. Considering that the limited therapeutic options for HCC, novel therapeutic targets and drugs are urgently needed. In this study, we discovered that 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP), isolated from the traditional Chinese medicinal herb, Garcinia oblongifolia, effectively inhibited cell growth and induced the caspase-dependent mitochondrial apoptosis in HCC. A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics were performed to find the molecular targets of TDP in HCC cells. Eighteen proteins were identified as differently expressed, with Hsp27 protein being one of the most significantly down-regulated proteins induced by TDP. In addition, the following gain- and loss-of-function studies indicated that Hsp27 mediates mitochondrial apoptosis induced by TDP. Furthermore, a nude mice model also demonstrated the suppressive effect of TDP on HCC. Our study suggests that TDP plays apoptosis-inducing roles by strongly suppressing the Hsp27 expression that is specifically associated with the mitochondrial death of the caspase-dependent pathway. In conclusion, TDP may be a potential anti-cancer drug candidate, especially to cancers with an abnormally high expression of Hsp27.
Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China.
Wei-ming
WM
Fu
Jin-fang
JF
Zhang
Hua
H
Wang
Zhi-chao
ZC
Xi
Wei-mao
WM
Wang
Peng
P
Zhuang
Xiao
X
Zhu
Shih-chi
SC
Chen
Tak-ming
TM
Chan
Kwong-Sak
KS
Leung
Gang
G
Lu
Hong-Xi
HX
Xu
Hsiang-fu
HF
Kung
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D005260:Female; D029760:Garcinia / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis*; D006360:Heat-Shock Proteins; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D040901:Proteomics / Q000379:methods; D014183:Transplantation, Heterologous; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C576555:1,3,5-trihydroxy-13,13-dimethyl-2H-pyran(7,6-b)xanthone; D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D044004:Xanthones; D020169:Caspases