Understanding molecular mechanisms of cancer cell-specific extracellular vesicle secretion

抄録

Extracellular vesicle (EV) secretion in cancer cells has been shown to have a significant impact on cancer progression, and the EV secretion is enhanced as compared to normal cells. We have previously reported on the secretory pathway of EVs specific to prostate cancer cell lines. However, the secretory pathway of EVs common to cancer cells is still unknown. We screened two cell lines using miRNA libraries and newly identified miR-891b and its target gene, phosphotransferase 1 (PSAT1), as regulators of EV secretion. PSAT1 is a metabolic enzyme in serine synthesis, and serine consumption is generally enhanced in cancer cells. PSAT1 expression is elevated in many cancer tissues, and we found that knockdown of PSAT1 suppressed EV secretion in cancer cell lines. This suggests that PSAT1-mediated EV secretion is a pathway common to multiple cancer types. Next, we examined PSAT1 expression in highly metastatic lines (lung, lymph node, and bone metastases) established from breast cancer cell lines, and found that PSAT1 expression was increased and EV secretion was enhanced in each highly metastatic line. The effect of PSAT1 on bone metastasis of breast cancer was investigated, and the data showed that PSAT1 overexpressing cancer cells markedly activated osteoclasts and promoted bone metastasis. These results suggest that serine metabolism is upregulated in many cancer cells and contributes to the secretion of EVs that have the function of promoting metastasis.