title: Sorcin induces a drug-resistant phenotype in human colorectal cancer by modulating Ca(2+) homeostasis.
abstract: The Ca(2+)-binding protein sorcin regulates intracellular calcium homeostasis and plays a role in the induction of drug resistance in human cancers. Recently, an 18 kDa mitochondrial isoform of sorcin was reported to participate in antiapoptosis in human colorectal cancer (CRC), but information remains lacking about the functional role of the more abundant 22 kDa isoform of sorcin expressed in CRC. We found the 22 kDa isoform to be widely expressed in human CRC cells, whether or not they were drug resistant. Its upregulation in drug-sensitive cells induced resistance to 5-fluorouracil, oxaliplatin, and irinotecan, whereas its downregulation sensitized CRC cells to these chemotherapeutic agents. Sorcin enhances the accumulation of Ca(2+) in the endoplasmic reticulum (ER), preventing ER stress, and, in support of this function, we found that the 22 kDa isoform of sorcin was upregulated under conditions of ER stress. In contrast, RNAi-mediated silencing of sorcin activated caspase-3, caspase-12, and GRP78/BiP, triggering apoptosis through the mitochondrial pathway. Our findings establish that CRC cells overexpress sorcin as an adaptive mechanism to prevent ER stress and escape apoptosis triggered by chemotherapeutic agents, prompting its further investigation as a novel molecular target to overcome MDR.
authors: Department of Medical Sciences, University of Foggia, Foggia, Italy.
authors: Francesca
authors: F
authors: Maddalena
authors: Gabriella
authors: G
authors: Laudiero
authors: Annamaria
authors: A
authors: Piscazzi
authors: Agnese
authors: A
authors: Secondo
authors: Antonella
authors: A
authors: Scorziello
authors: Valentina
authors: V
authors: Lombardi
authors: Danilo Swann
authors: DS
authors: Matassa
authors: Alberto
authors: A
authors: Fersini
authors: Vincenzo
authors: V
authors: Neri
authors: Franca
authors: F
authors: Esposito
authors: Matteo
authors: M
authors: Landriscina
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008970:Molecular Weight; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D020033:Protein Isoforms; C503113:SRI protein, human; D053454:Caspase 12; D053148:Caspase 3; D002118:Calcium