Cucurbitacin D Is a Disruptor of the HSP90 Chaperone Machinery

Journal of Natural Products
Jessica A HallB S J Blagg

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-isoc...Continue Reading

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Citations

Jun 14, 2016·Biochimie·Sharad VermaAbhinav Grover
Nov 9, 2016·Scientific Reports·Mohammed SikanderMeena Jaggi
Oct 27, 2017·Journal of Complementary & Integrative Medicine·Atefe GhahremanlooZabihullah Mohaqiq
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Apr 3, 2020·Phytotherapy Research : PTR·Christian Bailly
Sep 15, 2019·Bioorganic & Medicinal Chemistry·David Bickel, Holger Gohlke
Jan 24, 2020·European Journal of Medicinal Chemistry·Thadeu E M M CostaCarmen Penido
Apr 17, 2021·Future Medicinal Chemistry·Theodora ChatzisideriVasiliki Sarli

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