title: Implication of transcriptional repression in compound C-induced apoptosis in cancer cells.
abstract: Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to induce apoptosis in some types of cells. However, the underlying mechanisms remain largely unclear. Using a DNA microarray analysis, we found that the expression of many genes was downregulated upon treatment with compound C. Importantly, compound C caused transcriptional repression with the induction of p53, a well-known marker of transcriptional stress response, in several cancer cell lines. Compound C did not induce the phosphorylation of p53 but dramatically increased the protein level of p53 similar to some other transcriptional inhibitors, including 5,6-dichloro-1-β-D-ribobenzimidazole (DRB). Consistent with previous reports, we found that compound C initiated apoptotic death of cancer cells in an AMPK-independent manner. Similar to DRB and actinomycin D (ActD), two classic transcription inhibitors, compound C not only resulted in the loss of Bcl-2 and Bcl-xl protein but also induced the phosphorylation of eukaryotic initiation factor-alpha (eIF2α) on Ser51. Hence, the phosphorylation of eIF2α might be a novel marker of transcriptional inhibition. It is noteworthy that compound C-mediated apoptosis of cancer cells is correlated with decreased expression of Bcl-2 and Bcl-xl and the phosphorylation of eIF2α on Ser51. Remarkably, compound C exhibits potent anticancer activities in vivo. Taken together, our data suggest that compound C may be an attractive candidate for anticancer drug development.
authors.affiliation: 1] The Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan 646000, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China [3] Department of Hepatobiliary Surgery of the Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: R Y
authors.initials: RY
authors.lastname: Dai
authors.forename: X F
authors.initials: XF
authors.lastname: Zhao
authors.forename: J J
authors.initials: JJ
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: Z L
authors.initials: ZL
authors.lastname: Luo
authors.forename: L X
authors.initials: LX
authors.lastname: Yu
authors.forename: S K
authors.initials: SK
authors.lastname: Chen
authors.forename: C Y
authors.initials: CY
authors.lastname: Zhang
authors.forename: C Y
authors.initials: CY
authors.lastname: Duan
authors.forename: Y P
authors.initials: YP
authors.lastname: Liu
authors.forename: C H
authors.initials: CH
authors.lastname: Feng
authors.forename: X M
authors.initials: XM
authors.lastname: Xia
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Fu
authors.forename: H Y
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D011720:Pyrazoles; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C516138:dorsomorphin