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

Jung Rock Moon, Shin Ju Oh, Chang Kyun Lee, Sung-Gil Chi, Hyo Jong Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2117-2126
Number of pages10
JournalInternational Journal of Oncology
Volume54
Issue number6
DOIs
Publication statusPublished - 2019 Jun 1

Fingerprint

Transforming Growth Factors
Colon
Apoptosis
Neoplasms
Colorectal Neoplasms
Mitogen-Activated Protein Kinase Kinases
Etoposide
Epigenomics
Carcinogens
Colonic Neoplasms
Transcription Factors
Phosphotransferases
Epithelial Cells
Cytokines
Growth

Keywords

  • Cell apoptosis
  • Colon tumor
  • Ras/extracellular signal‑regulated kinase signaling pathway
  • Transforming growth factor-β1
  • XIAP‑associated factor 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

TGF-β1 protects colon tumor cells from apoptosis through XAF1 suppression. / Rock Moon, Jung; Ju Oh, Shin; Kyun Lee, Chang; Chi, Sung-Gil; Jong Kim, Hyo.

In: International Journal of Oncology, Vol. 54, No. 6, 01.06.2019, p. 2117-2126.

Research output: Contribution to journalArticle

Rock Moon, Jung ; Ju Oh, Shin ; Kyun Lee, Chang ; Chi, Sung-Gil ; Jong Kim, Hyo. / TGF-β1 protects colon tumor cells from apoptosis through XAF1 suppression. In: International Journal of Oncology. 2019 ; Vol. 54, No. 6. pp. 2117-2126.
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abstract = "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.",
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