PTPN6 promotes chemosensitivity of colorectal cancer cells via inhibiting the SP1/MAPK signalling pathway

Abstract

The abnormal expression of protein tyrosine phosphatase nonreceptor type 6 (PTPN6) has been proved to be associated with the progression of colorectal cancer. However, its role in chemosensitivity and related molecular mechanism have not been clarified. It has been reported that PTPN6 was down-regulated in colorectal cancer cells compared with the normal colorectal cells. To evaluate the effects of PTPN6 on the proliferation and survival of colorectal cancer cells, PTPN6 was overexpressed in colorectal cancer cells in the present study. We found that cell proliferation and viability were both decreased after overexpression of PTPN6. The IC50 of 5-Fu against colorectal cells was also declined in PTPN6 transfected cells. And further, we verified that PTPN6 could down-regulate the expression of P-gp and MRP-1. Moreover, SP1 was the target protein of PTPN6 predicated by ChIPBase software and confirmed through Co-immunoprecipitation assay and it was negatively regulated by PTPN6. To further verify the effect of SP1 on chemoresistance, SP1 was overexpressed. SP1 overexpression enhanced the drug-resistance to 5-Fu and abrogated the effects of PTPN6 upregulation on 5-Fu resistance. All the above changes were associated with the down-regulation of proteins related to MAPK signalling pathway, such as phosphorylation of extracellular regulated protein kinases (ERK) and p38. In summary, PTPN6 promoted chemosensitivity of colorectal cancer cells by targeting SP1 and inhibiting the activation of MAPK signalling pathway. SIGNIFICANCE OF THE STUDY: It has been demonstrated that the abnormal expression of PTPN6 was related to the progression of colorectal cancer. However, the chemosensitivity of PTPN6 and its molecular mechanisms were still unclear. Here, we identified that PTPN6 was down-regulated in colorectal cancer cells. Moreover, PTPN6 overexpression not only reduced cell proliferation and viability, but decreased the resistance of colorectal cells to 5-Fu. In our research, we found that the SP1 was the target protein of PTPN6 and it was negatively regulated by PTPN6. In addition, SP1 could increase the resistance of colorectal cells to 5-Fu. Molecular mechanism studies have shown that PTPN6 promoted the chemosensitivity of colorectal cancer cells by inhibiting the activation of MAPK signalling pathway.

Keywords: MAPK signalling pathway; PTPN6; SP1; chemosensitivity; colorectal cancer.