Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

• Published in: Cell death and differentiation Vol. 15; no. 2; pp. 274 - 282
• Main Authors: Tufi, R, Panaretakis, T, Bianchi, K, Criollo, A, Fazi, B, Di Sano, F, Tesniere, A, Kepp, O, Paterlini-Brechot, P, Zitvogel, L, Piacentini, M, Szabadkai, G, Kroemer, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2008; Nature Publishing Group
• Subjects: Anthracyclines - pharmacology; Apoptosis; Biochemistry; Biomedical and Life Sciences; Brefeldin A - pharmacology; Calcium - metabolism; Calreticulin - metabolism; Cancer; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Cell Membrane - metabolism; Chemotherapy; Dendritic cells; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; HeLa Cells; Homeostasis; Humans; Life Sciences; Ligands; Medicin och hälsovetenskap; Nerve Tissue Proteins - metabolism; Neuroblastoma; original-paper; Plasma; Protein Synthesis Inhibitors - pharmacology; Proteins; Stem Cells; France; calcium homeostasis; immunogenic cell death; reticulon 1C
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4402275

Some chemotherapeutic agents can elicit apoptotic cancer cell death, thereby activating an anticancer immune response that influences therapeutic outcome. We previously reported that anthracyclins are particularly efficient in inducing immunogenic cell death, correlating with the pre-apoptotic exposure of calreticulin (CRT) on the plasma membrane surface of anthracyclin-treated tumor cells. Here, we investigated the role of cellular Ca 2+ homeostasis on CRT exposure. A neuroblastoma cell line (SH-SY5Y) failed to expose CRT in response to anthracyclin treatment. This defect in CRT exposure could be overcome by the overexpression of Reticulon-1C, a manipulation that led to a decrease in the Ca 2+ concentration within the endoplasmic reticulum lumen. The combination of Reticulon-1C expression and anthracyclin treatment yielded more pronounced endoplasmic reticulum Ca 2+ depletion than either of the two manipulations alone. Chelation of intracellular (and endoplasmic reticulum) Ca 2+ , targeted expression of the ligand-binding domain of the IP 3 receptor and inhibition of the sarco-endoplasmic reticulum Ca 2+ -ATPase pump reduced endoplasmic reticulum Ca 2+ load and promoted pre-apoptotic CRT exposure on the cell surface, in SH-SY5Y and HeLa cells. These results provide evidence that endoplasmic reticulum Ca 2+ levels control the exposure of CRT.