TGF-β1 protects colon tumor cells from apoptosis through XAF1 suppression

Transforming growth factor-β1 (TGF-β1) 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‑β1 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‑β1 is linked to its regulatory effect on XAF1 induction in human colon cancer cells under stressful conditions. The results revealed that TGF‑β1 treatment protected tumor cells from various apoptotic stresses, including 5‑fluorouracil, etoposide and γ‑irradiation. XAF1 expression was activated at the transcriptional level by these apoptotic stresses and TGF‑β1 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‑β1 blocked the stress‑mediated XAF1 promoter activation and induction of apoptosis. This effect was abrogated if Erk1/2 was depleted, indicating that TGF‑β1 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‑β1, which may be utilized in the development of a novel therapeutic strategy for the treatment of colorectal cancer.