Hispidulin sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by AMPK activation leading to Mcl-1 block in translation.
Whether hispidulin, a flavone from traditional Chinese medicine, can modulate the anticancer effects of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), the cytokine currently in clinical trials was investigated. In the present study, we found that hispidulin potentiated the TRAIL-induced apoptosis in human ovarian cancer cells and converted TRAIL-resistant cells to TRAIL-sensitive cells. When examined for its mechanism, we found that hispidulin was highly effective in activation of caspases 8 and caspase 3 and consequent poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, we found that hispidulin downregulated the expression of Mcl-1, Bcl-2, and Bcl-xL. Whereas the downregulation of Bcl-2 and Bcl-xL was less pronounced, the downregulation of Mcl-1 was quite dramatic and was time-dependent. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. Interestingly, we determined that AMPK is activated upon hispidulin treatment, resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease. Therefore, our results show a novel mechanism for the sensitization to TRAIL-induced apoptosis linking hispidulin treatment to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of death receptor (DR) ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.
Yang
Jung-Mu
JM
Institute of Biochemistry, College of Life Science, National Chung Hsing University, Taichung, Taiwan.
Hung
Chao-Ming
CM
Fu
Chen-Nan
CN
Lee
Jang-Chang
JC
Huang
Chi-Hung
CH
Yang
Muh-Hwa
MH
Lin
Chih-Li
CL
Kao
Jung-Yie
JY
Way
Tzong-Der
TD
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D047309:Flavones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D055372:AMP-Activated Protein Kinases; C055957:hispidulin