Sorcin induces a drug-resistant phenotype in human colorectal cancer by modulating Ca 2+ homeostasis

Francesca Maddalena, Gabriella Laudiero, Annamaria Piscazzi, Agnese Secondo, Antonella Scorziello, Valentina Lombardi, Danilo Swann Matassa, Alberto Fersini, Vincenzo Neri, Franca Esposito, Matteo Landriscina

Research output: Contribution to journalArticlepeer-review

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 drugsensitive 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.

Original languageEnglish
Pages (from-to)7659-7669
Number of pages11
JournalCancer Research
Volume71
Issue number24
DOIs
Publication statusPublished - Dec 15 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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