Canine osteosarcoma cells exhibit basal accumulation of multiple chaperone proteins and are sensitive to small molecule inhibitors of GRP78 and heat shock protein function

Cell Stress Chaperones. 2022 May;27(3):223-239. doi: 10.1007/s12192-022-01263-3. Epub 2022 Mar 4.

Abstract

Osteosarcoma is the most common type of bone cancer in dogs and humans, with significant numbers of patients experiencing treatment failure and disease progression. In our search for new approaches to treat osteosarcoma, we previously detected multiple chaperone proteins in the surface-exposed proteome of canine osteosarcoma cells. In the present study, we characterized expression of representative chaperones and find evidence for stress adaptation in canine osteosarcoma cells relative to osteogenic progenitors from normal bone. We compared the cytotoxic potential of direct (HA15) and putative (OSU-03012) inhibitors of Grp78 function and found canine POS and HMPOS osteosarcoma cells to be more sensitive to both compounds than normal cells. HA15 and OSU-03012 increased the thermal stability of Grp78 in intact POS cells at low micromolar concentrations, but each induced distinct patterns in Grp78 expression without significant change in Grp94. Both inhibitors were as effective alone as carboplatin and showed little evidence of synergy in combination treatment. However, HMPOS cells with acquired resistance to carboplatin were sensitive to inhibition of Grp78 (by HA15; OSU-03012), Hsp70 (by VER-155008), and Hsp90 (by 17-AAG) function. These results suggest that multiple nodes within the osteosarcoma chaperome may be relevant chemotherapeutic targets against platinum resistance.

Keywords: AR-12; BiP; Chaperome; HA15; HSP5A; OSU-03012; Proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Neoplasms* / drug therapy
  • Carboplatin
  • Cell Line, Tumor
  • Dogs
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Chaperones / metabolism
  • Osteosarcoma* / drug therapy

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Carboplatin