Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9

Abstract

Cancer cells are commonly more resistant to cell death activated by the membranolytic protein complex C5b-9. Several surface-expressed and intracellular proteins that protect cells from complement-dependent cytotoxicity (CDC) have been identified. In this study, we investigated the function of heat shock protein 90 (Hsp90), an essential and ubiquitously expressed chaperone, overexpressed in cancer cells, in C5b-9-induced cell death. As shown, inhibition of Hsp90 with geldanamycin or radicicol is enhancing sensitivity of K562 erythroleukemia cells to CDC. Similarly, Hsp90 inhibition confers in Ramos B cell lymphoma cells elevated sensitivity to treatment with rituximab and complement. C5b-9 deposition is elevated on geldanamycin-treated cells. Purified Hsp90 binds directly to C9 and inhibits zinc-induced C9 polymerization, indicating that Hsp90 may act directly on the C5b-9 complex. Mortalin, also known as stress protein 70 or GRP75, is a mitochondrial chaperone that confers resistance to CDC. The postulated cooperation between Hsp90 and mortalin in protection from CDC was tested. Geldanamycin failed to sensitize toward CDC cells with knocked down mortalin. Direct binding of Hsp90 to mortalin was shown by co-immunoprecipitation in cell extracts after triggering with complement as well as by using purified recombinant proteins. These results provide an insight into the protective mechanisms utilized by cancer cells to evade CDC. They suggest that Hsp90 protects cells from CDC by inhibiting, together with mortalin, C5b-9 assembly and/or stability at the plasma membrane.

Context-dependent roles of complement in cancer

“…However, cancer cells adapt escape mechanisms for MAC. Hsp90 protected tumor cells from complement-dependent cytotoxicity by inhibiting, together with mortalin, C5b-9 assembly and/or stability at the plasma membrane 9 .…”

Complement System: Promoter or Suppressor of Cancer Progression?

“…MAC blockage can also be triggered by the Heat shock protein 90 (Hsp90). This protein directly interacts with the C9 molecules, are sequestered, preventing the polymerization and formation of the MAC [71]. Table 2.…”

Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation

“…As a molecular chaperone, the main function of HSP90 is to regulate the stability and activity of the client protein, which is pivotal for maintaining cell structure and function and inhibiting apoptosis 27,28 . Recent studies have shown that HSP90 binds to the chaperone-mortalin protein to attenuate complementmediated cell lysis 29 , while HSP90 inhibitors promote this process 14,15 . Therefore, HSP90 is an emerging therapeutic target in I/R injury and cardioprotection 12,13 .…”