Multi-kinase inhibitors can associate with heat shock proteins through their NH2-termini by which they suppress chaperone function

Oncotarget
Laurence BoothPaul Dent

Abstract

We performed proteomic studies using the GRP78 chaperone-inhibitor drug AR-12 (OSU-03012) as bait. Multiple additional chaperone and chaperone-associated proteins were shown to interact with AR-12, including: GRP75, HSP75, BAG2; HSP27; ULK-1; and thioredoxin. AR-12 down-regulated in situ immuno-fluorescence detection of ATP binding chaperones using antibodies directed against the NH2-termini of the proteins but only weakly reduced detection using antibodies directed against the central and COOH portions of the proteins. Traditional SDS-PAGE and western blotting assessment methods did not exhibit any alterations in chaperone detection. AR-12 altered the sub-cellular distribution of chaperone proteins, abolishing their punctate speckled patterning concomitant with changes in protein co-localization. AR-12 inhibited chaperone ATPase activity, which was enhanced by sildenafil; inhibited chaperone - chaperone and chaperone - client interactions; and docked in silico with the ATPase domains of HSP90 and of HSP70. AR-12 combined with sildenafil in a GRP78 plus HSP27 -dependent fashion to profoundly activate an eIF2α/ATF4/CHOP/Beclin1 pathway in parallel with inactivating mTOR and increasing ATG13 phosphorylation, collectively resultin...Continue Reading

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Citations

Jul 6, 2016·Frontiers in Oncology·Mehrad TavallaiPaul Dent
Sep 12, 2018·Journal of Cellular Physiology·Laurence BoothPaul Dent
Jan 16, 2017·Oncotarget·Laurence BoothPaul Dent
Nov 16, 2017·Oncotarget·Laurence BoothPaul Dent
Nov 12, 2019·Expert Opinion on Therapeutic Targets·Laurence BoothPaul Dent
Aug 6, 2019·Frontiers in Oncology·Laurence BoothPaul Dent
Aug 17, 2021·Anti-cancer Drugs·Paul DentJohn F Hancock
Sep 24, 2020·Biochemical Pharmacology·Jonathan O RaynerPaul Dent

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Methods Mentioned

BETA
transfection
gel filtration
nucleotide exchange
electrophoresis

Clinical Trials Mentioned

NCT02466802
NCT01817751

Software Mentioned

Hermes system
NAMD
Odyssey
CGenFF
Adobe Photoshop
Autodock Vina
PowerPoint

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