The double inhibition of PDK1 and STAT3-Y705 prevents liver metastasis in colorectal cancer

Abstract

As a key glycolysis enzyme, the significance of pyruvate dehydrogenase kinase 1 (PDK1) in the development of colorectal cancer (CRC) remains unknown. This study revealed that the prognosis of CRC patients with high levels of PDK1 was poor, and PDK1 knockdown significantly reduced liver metastasis of CRC in both nude mice and immune competent BALB/C mice. When combined with cryptotanshinone (CPT), an inhibitor of STAT3-p-Y705, the liver metastasis was further inhibited. PDK1 knockdown obviously increased reactive oxygen species level in anoikis conditions and subsequently resulted in an elevated anoikis, but the combination of PDK1 knockdown and CPT showed a reduced effect on anoikis. Based on this discrepancy, the adherence ability of CRC cells to matrix protein fibronectin was further detected. It showed that PDK1 knockdown significantly decreased the adherence of CRC cells to fibronectin when combined with CPT. These results suggest that inhibition of PDK1 can decrease the surviving CRC cells in blood circulation via up-regulation of anoikis, and inhibition of STAT3-p-Y705 can prevent it to settle down on the liver premetastatic niche, which ultimately reduces liver metastasis.