6717

SRI

Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44(+)/CD24(-) and ALDH1(high) cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial-mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer.

Sorcin, a soluble resistance-related calcium-binding protein, belongs to the small penta-EF-hand family. Recent study reported that upregulation of sorcin correlated with metastasis and poor prognosis of colorectal cancer (CRC). In the present study, we explored the regulatory role of sorcin in CRC metastasis. To investigate the role of sorcin in CRC metastasis, sorcin overexpressed with empty vector as control in CRC cell line (HCT116). The effect of sorcin overexpression on cell migration and invasion was evaluated via wound healing and transwell assay, respectively. Sorcin-induced changes in EMT process were evaluated by estern blot. Furthermore, the role of PI3K/Akt in the regulatory effect of sorcin on cell migration and invasion, and EMT process was explored by suppressing Akt activity in sorcin-overexpressed HCT116 cells. Sorcin overexpression in HCT116 cells resulted in a significant increase in cell migration and invasion. Sorcin overexpression also markedly promoted the EMT process. More importantly, our results revealed that sorcin stimulated EMT process through activating PI3K/Akt signaling. In summary, this study indicated that the promoting effect of sorcin on CRC metastasis was, at least in part, through PI3K/Akt signaling. The findings in this study highlight the effectiveness and therapeutic potential to utilize sorcin-targeted strategies in the treatment of CRC.