FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

Mol Cancer Ther. 2017 Sep;16(9):1979-1988. doi: 10.1158/1535-7163.MCT-17-0032. Epub 2017 Jun 15.

Abstract

Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1-selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3β/FBW7-dependent Mcl-1 degradation in killing of colorectal cancer cells by Hsp90 inhibitors and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy. Mol Cancer Ther; 16(9); 1979-88. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Heterografts
  • Humans
  • Mice
  • Mutation
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Proteolysis
  • RNA, Small Interfering / genetics

Substances

  • Antineoplastic Agents
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • HSP90 Heat-Shock Proteins
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • RNA, Small Interfering
  • Glycogen Synthase Kinase 3 beta
  • Proteasome Endopeptidase Complex