Mycoepoxydiene, a fungal polyketide inhibits MCF-7 cells through simultaneously targeting p53 and NF-κB pathways.
Mycoepoxydiene (MED) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp. HLY-1, which is associated with mangroves; however, the mechanism of action of MED remains unknown. Here, we report the molecular mechanisms of apoptosis activation and growth inhibition induced by MED in MCF-7 cells. The present results show that MED induces DNA damage through the production of reactive oxygen species (ROS), which resulted in the phosphorylation of H2AX and the activation of the Ataxia telangiectasia mutated kinase (ATM) and p53 signaling pathways. In addition, MED increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27, which eventually resulted in the inhibition of TNF-α-induced NF-κB transactivation. Therefore, we conclude that MED inhibits MCF-7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF-κB to disrupt cell proliferation. Because small molecules having both of these effects are rare, further exploration of MED as an antitumor lead compound is needed.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, PR China.
Jifeng
J
Wang
Baobing
B
Zhao
Yuting
Y
Yi
Wei
W
Zhang
Xuan
X
Wu
Lianru
L
Zhang
Yuemao
Y
Shen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001203:Ascomycota / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D055551:HSP27 Heat-Shock Proteins; D016328:NF-kappa B; D011753:Pyrones; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C476085:mycoepoxydiene