Induction of Rad51 protein levels by p38 MAPK decreases cytotoxicity and mutagenicity in benzo[a]pyrene-exposed human lung cancer cells.
Rad51 is an essential component of the homologous recombination repair pathway. Abnormal expression of Rad51 has been reported in various carcinomas. Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in the environment, induces cancer in multiple organs. B[a]P has been shown to activate the p38 MAPK signaling pathway in mammalian cells. The prime purpose of this study was to determine how B[a]P activates the p38 MAPK signaling pathway, and how this then regulates Rad51 expression in human cancer cells. Exposure of human lung cancer cells with B[a]P increased Rad51 protein levels in a time- and dose-dependent fashion. B[a]P also induced Rad51 mRNA and protein synthesis. Blockage of p38 MAPK activation by SB202190 or small interfering RNA (si-p38) decreased B[a]P-elicited Rad51 protein levels by increasing Rad51 protein instability, but did not affect Rad51 mRNA transcription. Furthermore, enhancement of p38 MAPK signaling by constitutively active MKK6 (MKK6E) increased Rad51 protein levels and protein stability. Moreover, B[a]P-induced cytotoxicity and mutagenicity were significantly increased in cells depleted of endogenous Rad51. Taken together, these results indicate that Rad51 protein provides a critical role in inhibiting the cytotoxicity and mutagenicity of B[a]P in B[a]P-treated human lung cancer cells. Furthermore, the work points to an unexpected role of p38 MAPK signaling in the control of Rad51 protein stability in response to B[a]P exposure.
Chuang
Show-Mei
SM
Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan.
Wang
Lyu-Han
LH
Hong
Jhao-Hao
JH
Lin
Yun-Wei
YW
D001564:Benzo(a)pyrene / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D020935:MAP Kinase Signaling System; D009153:Mutagens / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051135:Rad51 Recombinase / Q000737:chemistry / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D009153:Mutagens; D012333:RNA, Messenger; D001564:Benzo(a)pyrene; D048051:p38 Mitogen-Activated Protein Kinases; D051135:Rad51 Recombinase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease