TGF-beta 1 protects colon tumor cells from apoptosis through XAF1 suppression

Abstract

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine that functions as a growth suppressor in normal epithelial cells and early stage tumors, but acts as a tumor promoter during malignant progression. However, the molecular basis underlying the conversion of TGF-beta 1 function remains largely undefined. X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor that frequently displays epigenetic inactivation in various types of human malignancies, including colorectal cancer. The present study explored whether the anti-apoptotic effect of TGF-beta 1 is linked to its regulatory effect on XAF1 induction in human colon cancer cells under stressful conditions. The results revealed that TGF-beta 1 treatment protected tumor cells from various apoptotic stresses, including 5-fluorouracil, etoposide and gamma-irradiation. XAF1 expression was activated at the transcriptional level by these apoptotic stresses and TGF-beta 1 blocked the stress-mediated activation of the XAF1 promoter. The study also demonstrated that mitogen-activated protein kinase kinase inhibition or extracellular signal-activated kinase (Erk)1/2 depletion induced XAF1 induction, while the activation of K-Ras (G12C) led to its reduction. In addition, TGF-beta 1 blocked the stress-mediated XAF1 promoter activation and induction of apoptosis. This effect was abrogated if Erk1/2 was depleted, indicating that TGF-beta 1 represses XAF1 transcription through Erk activation, thereby protecting tumor cells from apoptotic stresses. These findings point to a novel molecular mechanism underlying the tumor-promoting function of TGF-beta 1, which may be utilized in the development of a novel therapeutic strategy for the treatment of colorectal cancer.