title: p53-p66(shc)/miR-21-Sod2 signaling is critical for the inhibitory effect of betulinic acid on hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third cause of cancer-related death. Betulinic acid (BA) is a pentacyclic triterpene, possessing potential pro-apoptotic activities. The present study was designed to evaluate the effect of BA on tumor growth in mice and HCC cell proliferation in vitro. We found that BA dose-dependently inhibited tumor growth in mice induced by DEN plus CCl4 (D/C) and suppressed cell viability and proliferation in several HCC cell lines. In addition, BA increased mitochondrial ROS generation and mitochondrial dysfunction, activating molecular apoptotic events and leading to apoptotic cell death. p53 was increased by BA in D/C-treated mice and HCC cells and inhibition of p53 significantly suppressed the pro-apoptotic and anti-tumor effect of BA. Increase of p66(shc) was involved in the pro-apoptotic and anti-tumor effect of BA. Moreover, BA-induced increase of p66(shc) was dependent upon p53. Sod2 expression was reduced by BA treatment, and a Sod2 mimic (MnTBAP) significantly blocked the pro-apoptotic and anti-tumor effect of BA. Furthermore, miR-21 was increased by BA in D/C-treated mice and HCC cells and inhibition of miR-21 significantly suppressed the pro-apoptotic effect of BA. miR-21 inhibitor attenuated BA-induced decrease of Sod2 and p53 inhibitor blocked BA-induced increase of miR-21. These results demonstrated that p53 is responsible for the anti-tumor effect of BA through up-regulation of p66(shc) and miR-21 and down-regulation of Sod2 expression, leading to mitochondrial ROS accumulation and apoptosis. The p53-p66(shc)/miR-21-Sod2 signaling is critical for BA-inhibited tumor growth and cancer cell proliferation.
authors.affiliation: Jingyue Yang, Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: jingyue_yang11@163.com.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Qiu
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Jingyue Yang, Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jingyue Yang, Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D002251:Carbon Tetrachloride / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D011897:Random Allocation; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000094062:Betulinic Acid; D000099156:Superoxide Dismutase 2
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002251:Carbon Tetrachloride; D004052:Diethylnitrosamine; D035683:MicroRNAs; D053978:Pentacyclic Triterpenes; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D000094062:Betulinic Acid; D000099156:Superoxide Dismutase 2; C531950:MIRN21 microRNA, mouse; C528034:Shc1 protein, mouse
keywords: Apoptosis; Betulinic acid; Hepatocellular carcinoma; Sod2; p53; p66(shc)