Cyclin D1 induction by benzo[a]pyrene-7,8-diol-9,10-epoxide via the phosphatidylinositol 3-kinase/Akt/MAPK- and p70s6k-dependent pathway promotes cell transformation and tumorigenesis.
Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), the major metabolite of B[a]P, has been well recognized as one ubiquitous carcinogen, but the molecular mechanism involved in its carcinogenic effect remains obscure. In the present study, we found that bronchial epithelial cells (Beas-2B) and hepatocytes treated with B[a]PDE presented a significant increase of cyclin D1 expression. Moreover, Akt, p70(s6k), and MAPKs including JNK, Erks, and p38 were notably activated in B[a]PDE-treated Beas-2B cells, whereas NF-kappaB, NFAT, and Egr-1 were not. Our results demonstrated that JNK and Erks were required in B[a]PDE-induced cyclin D1 expression because the inhibition of JNK or Erks by a selective chemical inhibitor or dominant negative mutant robustly impaired the cyclin D1 induction by B[a]PDE. Furthermore, we found that overexpression of the dominant negative mutant of p85 (regulatory subunit of phosphatidylinositol 3-kinase) or Akt dramatically suppressed B[a]PDE-induced JNK and Erk activation as well as cyclin D1 expression, suggesting that cyclin D1 induction by B[a]PDE is via the phosphatidylinositol 3-kinase/Akt/MAPK-dependent pathway. In addition, we clarified that p70(s6k) is also involved in B[a]PDE-induced cyclin D1 expression because rampamycin pretreatment dramatically reduced cyclin D1 induction by B[a]PDE. More importantly, we demonstrated that up-regulated cyclin D1 by B[a]PDE plays a critical role in oncogenic transformation and tumorigenesis of Beas-2B cells. These results not only broaden our knowledge of the molecular mechanism of B[a]PDE carcinogenicity but also lead to the further study of chemoprevention of B[a]PDE-associated human cancers.
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Changzheng Hospital, China.
Jin
J
Ding
Beifang
B
Ning
Wenfeng
W
Gong
Wen
W
Wen
Kun
K
Wu
Junqing
J
Liang
Guoping
G
He
Shanna
S
Huang
Wen
W
Sun
Tao
T
Han
Lei
L
Huang
Guangwen
G
Cao
Mengchao
M
Wu
Weifen
W
Xie
Hongyang
H
Wang
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D019938:Cyclin D1; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus