title: Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia.
abstract: CLL is a disease characterized by chromosomal deletions, acquired copy number changes and aneuploidy. Recent studies have shown that overexpression of Heat Shock Factor (HSF) 1 in aneuploid tumor cells can overcome deficiencies in heat shock protein (HSP) 90-mediated protein folding and restore protein homeostasis. Interestingly, several independent studies have demonstrated that HSF1 expression and activity also affects the chaperoning of HSP90 kinase clients, although the mechanism underlying this observation is unclear. Here, we determined how HSF1 regulates HSP90 function using CLL as a model system. We report that HSF1 is overexpressed in CLL and treatment with triptolide (a small molecule inhibitor of HSF1) induces apoptosis in cultured and primary CLL B-cells. We demonstrate that knockdown of HSF1 or its inhibition with triptolide results in the reduced association of HSP90 with its kinase co-chaperone cell division cycle 37 (CDC37), leading to the partial depletion of HSP90 client kinases, Bruton's Tyrosine Kinase (BTK), c-RAF and cyclin-dependent kinase 4 (CDK4). Treatment with triptolide or HSF1 knockdown disrupts the cytosolic complex between HSF1, p97, HSP90 and the HSP90 deacetylase- Histone deacetylase 6 (HDAC6). Consequently, HSF1 inhibition results in HSP90 acetylation and abrogation of its chaperone function. Finally, tail vein injection of Mec-1 cells into Rag2-/-IL2Rγc-/- mice followed by treatment with minnelide (a pro-drug of triptolide), reduced leukemia, increased survival and attenuated HSP90-dependent survival signaling in vivo. In conclusion, our study provides a strong rationale to target HSF1 and test the activity of minnelide against human CLL.
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Trisha
authors.initials: T
authors.lastname: Home
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Abdulraheem
authors.initials: A
authors.lastname: Yacoub
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.affiliation: Georgia Regents University, Augusta, GA, USA.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dandawate
authors.affiliation: Interdisciplinary Science and Technology Research Academy, University of Pune, Pune, Maharashtra, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: McGuirk
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
mesh_terms: D000107:Acetylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010755:Organophosphates / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D010755:Organophosphates; D010616:Phenanthrenes; D034741:RNA, Small Interfering; D014157:Transcription Factors; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt
keywords: CLL; HSF1; HSP90; minnelide