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Conference Paper: Both p53 dependent and independent pathways contribute to RAD001 mediated enhancement of chemo-sensitivity in hepatocellular carcinoma

TitleBoth p53 dependent and independent pathways contribute to RAD001 mediated enhancement of chemo-sensitivity in hepatocellular carcinoma
Authors
Issue Date2007
PublisherAmerican Association for Cancer Research
Citation
AACR 98th Annual Meeting, Los Angeles, CA, 14–18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 448 How to Cite?
AbstractObjective: Chemo-resistance in hepatocellular carcinoma (HCC) hinders the application of systemic and local chemotherapy. Inhibition of mammalian target of rapamycin (mTOR) has been demonstrated to be able to sensitize tumor cells to cytotoxic drugs, but the mechanism remains unclear. Therefore, we design the present study to investigate the effects of mTOR inhibition on sensitization of HCC cells to chemo-cytotoxic drugs, with a focus on the potential interaction between mTOR and p53. Methods: In vitro, HCC cell lines with wild type (wt) p53 (HepG2), mutant/null p53 (PLC/Hep3B) and p53 stable transfectant (Hep3B-p53+) were treated with RAD001 alone, cisplatin alone or combination of RAD001 and cisplatin. Cell apoptosis was determined by Annexin V/ propidium iodine staining, and the molecular mechanism was explored by poly(ADP-ribose) polymerase (PARP) degradation. In vivo, the effects of RAD001 combined with cisplatin was evaluated in a HCC xenograft model. Results: The effect of mTOR inhibition was confirmed by dephosphorylation of 4E-BP1 and ribosomal protein S6. RAD001 enhanced cisplatin-induced PARP degradation and apoptosis in all the three cell lines tested. Transfection of p53 into Hep3B-p53- cell line could further enhance RAD001 mediated chemo-sensitization. RAD001, or cisplatin alone down-regulated the expression of pro-survival molecules, survivin, cyclin D1, and Bcl-2, and a synergistic effect was observed when RAD001 was combined with cisplatin. Prominent retardation of tumor growth was observed in the HCC xenografts treated with RAD001 and cisplatin. Conclusions: This study demonstrated that inhibition of mTOR enhanced cisplatin-induced chemo-cytotoxicity in HCC in both p53 dependent and independent manner.
Persistent Identifierhttp://hdl.handle.net/10722/107730
ISSN
2023 Impact Factor: 12.5
2023 SCImago Journal Rankings: 3.468

 

DC FieldValueLanguage
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorTam, KHen_HK
dc.contributor.authorYang, Zen_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2010-09-26T00:10:00Z-
dc.date.available2010-09-26T00:10:00Z-
dc.date.issued2007en_HK
dc.identifier.citationAACR 98th Annual Meeting, Los Angeles, CA, 14–18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 448-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/107730-
dc.description.abstractObjective: Chemo-resistance in hepatocellular carcinoma (HCC) hinders the application of systemic and local chemotherapy. Inhibition of mammalian target of rapamycin (mTOR) has been demonstrated to be able to sensitize tumor cells to cytotoxic drugs, but the mechanism remains unclear. Therefore, we design the present study to investigate the effects of mTOR inhibition on sensitization of HCC cells to chemo-cytotoxic drugs, with a focus on the potential interaction between mTOR and p53. Methods: In vitro, HCC cell lines with wild type (wt) p53 (HepG2), mutant/null p53 (PLC/Hep3B) and p53 stable transfectant (Hep3B-p53+) were treated with RAD001 alone, cisplatin alone or combination of RAD001 and cisplatin. Cell apoptosis was determined by Annexin V/ propidium iodine staining, and the molecular mechanism was explored by poly(ADP-ribose) polymerase (PARP) degradation. In vivo, the effects of RAD001 combined with cisplatin was evaluated in a HCC xenograft model. Results: The effect of mTOR inhibition was confirmed by dephosphorylation of 4E-BP1 and ribosomal protein S6. RAD001 enhanced cisplatin-induced PARP degradation and apoptosis in all the three cell lines tested. Transfection of p53 into Hep3B-p53- cell line could further enhance RAD001 mediated chemo-sensitization. RAD001, or cisplatin alone down-regulated the expression of pro-survival molecules, survivin, cyclin D1, and Bcl-2, and a synergistic effect was observed when RAD001 was combined with cisplatin. Prominent retardation of tumor growth was observed in the HCC xenografts treated with RAD001 and cisplatin. Conclusions: This study demonstrated that inhibition of mTOR enhanced cisplatin-induced chemo-cytotoxicity in HCC in both p53 dependent and independent manner.-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Researchen_HK
dc.titleBoth p53 dependent and independent pathways contribute to RAD001 mediated enhancement of chemo-sensitivity in hepatocellular carcinomaen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.emailYang, Z: zfyang@hkucc.hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.identifier.hkuros128507en_HK
dc.identifier.issnl0008-5472-

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