title: Cucurbitacin D Is a Disruptor of the HSP90 Chaperone Machinery.
abstract: Heat shock protein 90 (Hsp90) facilitates the maturation of many newly synthesized and unfolded proteins (clients) via the Hsp90 chaperone cycle, in which Hsp90 forms a heteroprotein complex and relies upon cochaperones, immunophilins, etc., for assistance in client folding. Hsp90 inhibition has emerged as a strategy for anticancer therapies due to the involvement of clients in many oncogenic pathways. Inhibition of chaperone function results in client ubiquitinylation and degradation via the proteasome, ultimately leading to tumor digression. Small molecule inhibitors perturb ATPase activity at the N-terminus and include derivatives of the natural product geldanamycin. However, N-terminal inhibition also leads to induction of the pro-survival heat shock response (HSR), in which displacement of the Hsp90-bound transcription factor, heat shock factor-1, translocates to the nucleus and induces transcription of heat shock proteins, including Hsp90. An alternative strategy for Hsp90 inhibition is disruption of the Hsp90 heteroprotein complex. Disruption of the Hsp90 heteroprotein complex is an effective strategy to prevent client maturation without induction of the HSR. Cucurbitacin D, isolated from Cucurbita texana, and 3-epi-isocucurbitacin D prevented client maturation without induction of the HSR. Cucurbitacin D also disrupted interactions between Hsp90 and two cochaperones, Cdc37 and p23.
authors.affiliation: †Department of Medicinal Chemistry, The University Of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hall
authors.affiliation: †Department of Medicinal Chemistry, The University Of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Sahithi
authors.initials: S
authors.lastname: Seedarala
authors.forename: Nichole
authors.initials: N
authors.lastname: Rice
authors.forename: Lucas
authors.initials: L
authors.lastname: Kopel
authors.forename: Fathi
authors.initials: F
authors.lastname: Halaweish
authors.affiliation: †Department of Medicinal Chemistry, The University Of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D019662:Cucurbitaceae / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D061986:MCF-7 Cells; D018832:Molecular Chaperones; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D014157:Transcription Factors; D014315:Triterpenes; C038105:cucurbitacin D; C001277:geldanamycin