Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 160, Issue -, Pages 755-767Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2020.09.013
Keywords
BiP; Bortezomib; Endoplasmic reticulum; Glutathione; Glutathione S-Transferase; S-glutathionylation; Multiple myeloma; Reactive oxygen species; Redox; Unfolded protein response
Funding
- National Institutes of Health [CA08660, CA117259, S10OD010731, NCRR C06RR015455, NCRR P20RR024485]
- South Carolina Centers of Excellence program
- American Cancer Society Institutional Research Grant, from the American Cancer Society [IRG-19-137-20]
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Multiple myeloma (MM) cells have high rates of secretion of proteins rich in disulfide bonds and depend upon compartmentalized redox balance for accurate protein folding. The proteasome inhibitor bortezomib (Btz) is a successful frontline treatment for the disease, but its long-term efficacy is restricted by the acquisition of resistance. We found that MM cell lines resistant to Btz maintain high levels of oxidative stress and are cross resistant to endoplasmic reticulum (ER) stress-inducing agents thapsigargin (ThG), and tunicamycin (TuM). Moreover, cells expressing high/wild type levels of glutathione S-transferase P (GSTP) are more resistant than Gstp1/p2 knockout cells. In agreement, basal levels of S-glutathionylated proteins and redox regulation enzymes, including GSTP are elevated at mRNA and protein levels in resistant cells. GSTP mediated S-glutathionylation (SSG) regulates the activities of a number of redox active ER proteins. Here we demonstrated that the post translational modification determines the balance between foldase and ATPase activities of the binding immunoglobulin protein (BiP), with Cys41-SSG important for ATPase, and Cys420-SSG for foldase. BiP expression and S-glutathionylation are increased in clinical specimens of bone marrow from MM patients compared to noncancerous samples. Preventing S-glutathionylation in MM cells with a GSTP specific inhibitor restored BiP activities and reversed resistance to Btz. Therefore, S-glutathionylation of BiP confers pro-survival advantages and represents a novel mechanism of drug resistance in MM cells. We conclude that altered GSTP expression leads to S-glutathionylation of BiP, and contributes to acquired resistance to Btz in MM.
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