title: MsrB3 deficiency induces cancer cell apoptosis through p53-independent and ER stress-dependent pathways.
abstract: We have previously shown that down-regulation of methionine sulfoxide reductase B3 (MsrB3) induces cancer cell apoptosis through the activation of the intrinsic mitochondrial pathway. However, the mechanism through which MsrB3 deficiency results in cancer cell death is poorly understood. In this study, we investigated whether p53 and endoplasmic reticulum (ER) stress are involved in MsrB3 deficiency-induced cancer cell apoptosis using breast and colon cancer cells. MsrB3 depletion resulted in p53 down-regulation at the post-transcriptional level. MsrB3 deficiency induced cell death to a similar extent in both p53 wild-type (p53+/+) and null (p53-/-) cancer cells, suggesting that MsrB3 deficiency-induced apoptosis occurs independently of p53. MsrB3 deficiency significantly increased ER stress, which resulted in apoptosis. In addition, MsrB3 depletion activated the pro-apoptotic Bim molecule, which is essential for ER stress-induced apoptosis. MsrB3 deficiency increased cytosolic calcium levels, suggesting that MsrB3 down-regulation leads to a disturbance of calcium homeostasis in the ER, which consequently triggers ER stress. MsrB3 overexpression in MsrB3-depleted cells reduced ER stress, and was accompanied by at least partial recovery of cell viability. Taken together, our results suggest that MsrB3 plays a critical role in cancer cell apoptosis through the modulation of ER stress status.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Geun-Hee
authors.initials: GH
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address: hykim@ynu.ac.kr.
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
mesh_terms: D017209:Apoptosis; D059865:Endoplasmic Reticulum Stress; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051150:Methionine Sulfoxide Reductases / Q000235:genetics* / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051150:Methionine Sulfoxide Reductases; C524352:MSRB3 protein, human
keywords: Calcium homeostasis; Cancer; ER stress; Methionine sulfoxide; MsrB3; p53