Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo

Huanjie Shao, Chun Gao, Haikuo Tang, Hao Zhang, Lewis R. Roberts, Bonnie L. Hylander, Elizabeth A. Repasky, Wen W. Ma, Jingxin Qiu, Alex A. Adjei, Grace K. Dy, Chunrong Yu

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Background & Aims: The mammalian target of rapamycin (mTOR) plays a pivotal role in hepatocellular carcinoma (HCC). Previous studies indicated that inhibition of mTORC1 enhanced histone deacetylase inhibitors (HDACis)-mediated anti-tumor activity, accompanied with feedback activation of AKT. Therefore, dual targeting of mTORC1/C2 should be more efficient in suppressing AKT activity and in enhancing the anti-tumor activity of HDACi in HCC. Methods: The interactions between mTOR kinase inhibitors (mTORKis) (i.e., Pp242, AZD8055, OSI027) and HDACis (i.e., SAHA, LBH589) were examined in vitro using HCC cell lines and in vivo using patient-derived primary HCC xenografts on SCID mice. Results: mTORKis significantly enhanced HDACi-induced apoptosis in HCC cells. The inhibition of both mTORC1/2 not only efficiently blocked mTORC1 signaling, but also abrogated AKT-feedback activation caused by selective mTORC1 inhibition. The co-treatment of mTORKi and HDACi further inhibited AKT signaling and upregulated Bim. Dysfunction of mTORC2 by shRNA significantly lowered the threshold of HDACi-induced cytotoxicity by abrogating AKT activation. Knockdown of AKT1 sensitized Pp242/HDACi-induced apoptosis and ectopic expression of constitutively active AKT1 abrogated the combination-induced cytotoxicity, indicating AKT plays a vital role in the combination-induced effects. Knockdown of Bim prevented Pp242/HDACis-induced cytotoxicity in HCC. Lastly, in vivo studies indicated that the combination of AZD8055 and SAHA almost completely inhibited tumor-growth, without obvious adverse effects, by abrogating AKT and upregulating Bim; while either agent alone shows only 30% inhibition in primary HCC xenografts. Conclusions: Our findings suggest that a combining-regimen of mTORKi and HDACi may be an effective therapeutic strategy for HCC.

Original languageEnglish (US)
Pages (from-to)176-183
Number of pages8
JournalJournal of hepatology
Volume56
Issue number1
DOIs
StatePublished - Jan 1 2012

Keywords

  • AKT
  • Apoptosis
  • Bim
  • HCC
  • HDAC inhibitor
  • mTOR kinase inhibitor

ASJC Scopus subject areas

  • Hepatology

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