Concurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma

Int J Cancer. 2013 Oct 15;133(8):1813-24. doi: 10.1002/ijc.28206. Epub 2013 Jun 15.

Abstract

Mantle cell lymphoma (MCL) is an aggressive form of Non-Hodgkin-lymphoma (NHL) with an ongoing need for novel treatments. Apart from the translocation t(11:14), which facilitates constitutive transcription of cyclin D1, additional aberrations are frequently observed in MCL, including a recurrent dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. mTOR, a key component of this pathway, is pivotal for the assembly of mTOR complex (mTORC) 1 and 2. Temsirolimus, an analog of the mTOR inhibitor rapamycin, is approved for the treatment of relapsed MCL. Response rates, however, are low and response durations are short. We demonstrate that inhibition of mTORC1 by rapamycin or blocking of mTORC1 and mTORC2 in conjunction with PI3K by NVP-BEZ235 reduces proliferation of MCL cell lines to a similar extent. However, only NVP-BEZ235 is able to sufficiently inhibit the downstream pathway of mTOR and to mediate cell death through activation of the intrinsic apoptosis pathway. Further analysis demonstrated that the anti-apoptotic Bcl-2 family member Mcl-1 plays a central role in regulation of MCL survival. While Mcl-1 protein levels remained unchanged after coculture with rapamycin, they were down-regulated in NVP-BEZ235 treated cells. Furthermore, inhibition of Mcl-1 by the BH3-only mimetic obatoclax or down-regulation of constitutive Mcl-1, but not of Bcl-2 or Bcl-xL, by siRNA facilitated cell death of MCL cells and enhanced NVP-BEZ235's capacity to induce cell death. Our findings may help to lay the foundation for further improvements in the treatment of MCL.

Keywords: AKT; Mcl-1; PI3K; mTOR; mantle cell lymphoma; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Caspase Inhibitors / pharmacology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Humans
  • Imidazoles / pharmacology
  • Lymphoma, Mantle-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Multiprotein Complexes / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Pyrroles / pharmacology
  • Quinolines / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • bcl-X Protein / genetics

Substances

  • Amino Acid Chloromethyl Ketones
  • Antibiotics, Antineoplastic
  • Caspase Inhibitors
  • Imidazoles
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Quinolines
  • RNA, Small Interfering
  • bcl-X Protein
  • quinoline-val-asp(OMe)-CH2-OPH
  • Cyclin D1
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Caspases
  • obatoclax
  • dactolisib
  • Sirolimus