title: Heat shock factor 1 confers resistance to Hsp90 inhibitors through p62/SQSTM1 expression and promotion of autophagic flux.
abstract: Heat shock protein 90 (Hsp90) has an important role in many cancers. Biochemical inhibitors of Hsp90 are in advanced clinical development for the treatment of solid and hematological malignancies. At the cellular level, their efficacy is diminished by the fact that Hsp90 inhibition causes activation of heat shock factor 1 (HSF1). We report a mechanism by which HSF1 activation diminishes the effect of Hsp90 inhibitors geldanamycin and 17-allylaminogeldanamycin (17-AAG, tanespimycin). Silencing HSF1 with siRNA or inhibiting HSF1 activity with KRIBB11 lowers the threshold for apoptosis in geldanamycin and 17-AAG-treated cancer cells. Autophagy also mitigates the actions of Hsp90 inhibitors. Blocking autophagy with 3-methyladenine (3-MA), bafilomycin A1, or beclin 1 siRNA also lower the threshold for apoptosis. Exploring a potential relationship between HSF1 and autophagy, we monitored autophagosome formation and autophagic flux in control and HSF1-silenced cells. Results show HSF1 is required for autophagy in Hsp90 inhibitor-treated cells. The reduced autophagy observed in HSF1-silenced cells correlates with enhanced cell death. To investigate how HSF1 promotes autophagy, we monitored the expression of genes involved in the autophagic cascade. These data show that sequestosome 1 (p62/SQSTM1), a protein involved in the delivery of autophagic substrates and nucleation of autophagosomes, is an HSF1-regulated gene. Gene silencing was used to evaluate the significance of p62/SQSTM1 in Hsp90 inhibitor resistance. Cells where p62/SQSTM1 was silenced showed a dramatic increase in sensitivity to Hsp90 inhibitors. Results highlight the importance of HSF1 and HSF1-dependent p62/SQSTM1 expression in resistance Hsp90 inhibitors, underscoring the potential of targeting HSF1 to improve the efficacy of Hsp90 inhibitors in cancer.
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States.
authors.forename: Buddhini
authors.initials: B
authors.lastname: Samarasinghe
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States.
authors.forename: Christina T K
authors.initials: CT
authors.lastname: Wales
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Taylor
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States; University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, United States. Electronic address: jacobsa@hawaii.edu.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Jacobs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors
keywords: 17-AAG; 17-N-allylamino-17-demethoxygeldanamycin; ATG; Autophagy; Cancer; DMSO; HSE; HSF1; Hsp; Hsp90; LC3; SQSTM1; autophagy-related gene; dimethyl sulfoxide; heat shock element; heat shock factor 1; heat shock protein; microtubule-associated protein 1 light chain 3; p62/SQSTM1; sequestesome 1