Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1

Abstract Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the nucleus into the extracellular milieu. We previously showed that cisplatin mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is responsible for translocation of CRT to the plasma membrane. CT-HMGB2 is three orders of magnitude more potent than oxaliplatin at inducing CRT translocation. Inhibition of HMGB1 and HMGB2 secretion and/or their activation of nuclear factor-kappa B (NF-kB) has potential utility for treating cardiovascular, and neurodegenerative diseases; whereas CT-HMGB2 could augment therapeutic approaches to cancer treatment.