Switch of transforming growth factor [beta] function from tumor suppression to stimulation in adenomatous polyposis coli (APC) knocked-down human colon carcinoma cells

TGFβ exerts a potent tumor-suppressive effect in the human colon carcinoma CBS and Moser cells. However, TGFβ can also function as a tumor promoter. The mechanisms underlying the tumor promoting effect of TGFβ are not understood. Both the CBS and Moser cells were found to express mutant (truncated) APC. Expression of this form of APC did not interfere with the tumor-suppressive function of TGFβ. However, when APC expression was knocked down in these cells, TGFβ function switched from that of tumor suppression to that of tumor promotion. TGFβ stimulated cellular invasion and anchorage-independent growth in APC knocked-down cells. Knocking down APC expression abrogated the ability of TGFβ to induce the expression of the tumor suppressor E-cadherin and the cyclin dependent kinase inhibitor p21/Waf1. TGFβ now stimulated the constitutive TCF transcriptional activation activity associated with the β-catenin/Wnt pathway in the APC knocked-down cells. Thus, the level of APC expression determined the type of TGFβ function in these human colon carcinoma cells.