title: Drug transporter-independent liver cancer cell killing by a marine steroid methyl spongoate via apoptosis induction.
abstract: Hepatocellular carcinoma (HCC) is inherently resistant to the majority of clinical anticancer drugs. To obtain drugs that can circumvent or evade such inherent drug resistance of HCC, we investigated the effect of the marinely derived steroid methyl spongoate (MESP) on HCC cells. MESP displayed potent cell killing against a panel of six HCC cell lines, independent of their expression of drug transporters. MESP did not change the function of the drug transporters, and its cell killing was not impaired in multidrug-resistant cancer cells overexpressing the transporters. The cell killing of MESP was irrelevant to estrogen or androgen signaling and was not associated with cell cycle progression, inhibition of microtubules, and topoisomerases. In contrast, MESP potently induced apoptosis via activation of a proapoptotic caspase cascade and relief of the suppression of antiapoptotic signal transducers and activators of transcription 3 (STAT3) signaling. MESP inhibited the phosphorylation of STAT3, a critical survival signaling factor that reduced the expression of the antiapoptotic protein x-linked inhibitor of apoptosis protein but enhanced the expression of the proapoptotic protein Bax, thus promoting caspase-dependent apoptosis. These data reveal that MESP may well serve as an important candidate drug lead for HCC therapy.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.forename: Jing-Xu
authors.initials: JX
authors.lastname: Gong
authors.forename: Lin-Jiang
authors.initials: LJ
authors.lastname: Tong
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhao-Li
authors.initials: ZL
authors.lastname: Zhou
authors.forename: Hong-Chun
authors.initials: HC
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000728:Androgens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; C494826:BAX protein, human; D002352:Carrier Proteins; D004967:Estrogens; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013256:Steroids; D051028:bcl-2-Associated X Protein; D020169:Caspases