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

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

doi:10.3892/ijo.2019.4776

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

Authors:
- Jung Rock Moon
- Shin Ju Oh
- Chang Kyun Lee
- Sung Gil Chi
- Hyo Jong Kim
View Affiliations

Affiliations: Department of Internal Medicine, Division of Gastroenterology, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea, Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
Published online on: April 9, 2019 https://doi.org/10.3892/ijo.2019.4776
Pages: 2117-2126

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Eastham JA, Truong LD, Rogers E, Kattan M, Flanders KC, Scardino PT and Thompson TC: Transforming growth factor-beta 1: Comparative immunohistochemical localization in human primary and metastatic prostate cancer. Lab Invest. 73:628–635. 1995.PubMed/NCBI
2	Park BJ, Park JI, Byun DS, Park JH and Chi SG: Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer. Cancer Res. 60:3031–3038. 2000.PubMed/NCBI
3	Massagué J, Cheifetz S, Boyd FT and Andres JL: TGF-beta receptors and TGF-beta binding proteoglycans: Recent progress in identifying their functional properties. Ann NY Acad Sci. 593(1 Transforming): 59–72. 1990. View Article : Google Scholar : PubMed/NCBI
4	Heldin CH, Miyazono K and ten Dijke P: TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 390:465–471. 1997. View Article : Google Scholar : PubMed/NCBI
5	Massagué J, Seoane J and Wotton D: Smad transcription factors. Genes Dev. 19:2783–2810. 2005. View Article : Google Scholar : PubMed/NCBI
6	Mu Y, Gudey SK and Landström M: Non-Smad signaling pathways. Cell Tissue Res. 347:11–20. 2012. View Article : Google Scholar
7	Shi Y and Massagué J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 113:685–700. 2003. View Article : Google Scholar : PubMed/NCBI
8	Massagué J: A very private TGF-beta receptor embrace. Mol Cell. 29:149–150. 2008. View Article : Google Scholar : PubMed/NCBI
9	Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, et al: Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 268:1336–1338. 1995. View Article : Google Scholar : PubMed/NCBI
10	Tsushima H, Kawata S, Tamura S, Ito N, Shirai Y, Kiso S, Imai Y, Shimomukai H, Nomura Y, Matsuda Y, et al: High levels of transforming growth factor beta 1 in patients with colorectal cancer: Association with disease progression. Gastroenterology. 110:375–382. 1996. View Article : Google Scholar : PubMed/NCBI
11	Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S and Cohen A: High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev. 4:549–554. 1995.PubMed/NCBI
12	Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK and Chi SG: Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene. 22:4314–4332. 2003. View Article : Google Scholar : PubMed/NCBI
13	Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, Pasche B, Lee C and Grippo PJ: TGF-β: Duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 106:djt3692014. View Article : Google Scholar
14	Yan Z, Winawer S and Friedman E: Two different signal transduction pathways can be activated by transforming growth factor beta 1 in epithelial cells. J Biol Chem. 269:13231–13237. 1994.PubMed/NCBI
15	Javelaud D and Mauviel A: Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: Implications for carcinogenesis. Oncogene. 24:5742–5750. 2005. View Article : Google Scholar : PubMed/NCBI
16	Chin BY, Petrache I, Choi AM and Choi ME: Transforming growth factor beta1 rescues serum deprivation-induced apoptosis via the mitogen-activated protein kinase (MAPK) pathway in macrophages. J Biol Chem. 274:11362–11368. 1999. View Article : Google Scholar : PubMed/NCBI
17	Huang Y, Hutter D, Liu Y, Wang X, Sheikh MS, Chan AM and Holbrook NJ: Transforming growth factor-beta 1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities. J Biol Chem. 275:18234–18242. 2000. View Article : Google Scholar : PubMed/NCBI
18	Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science. 267:1456–1462. 1995. View Article : Google Scholar : PubMed/NCBI
19	Haq R and Zanke B: Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance. Cancer Metastasis Rev. 17:233–239. 1998. View Article : Google Scholar : PubMed/NCBI
20	Reed JC: Dysregulation of apoptosis in cancer. J Clin Oncol. 17:2941–2953. 1999. View Article : Google Scholar : PubMed/NCBI
21	Kaufmann SH and Vaux DL: Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene. 22:7414–7430. 2003. View Article : Google Scholar : PubMed/NCBI
22	Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ and Tsang BK: p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res. 63:7081–7088. 2003.PubMed/NCBI
23	Salvesen GS and Duckett CS: IAP proteins: Blocking the road to death’s door. Nat Rev Mol Cell Biol. 3:401–410. 2002. View Article : Google Scholar : PubMed/NCBI
24	Du C, Fang M, Li Y, Li L and Wang X: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 102:33–42. 2000. View Article : Google Scholar : PubMed/NCBI
25	Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K and Takahashi R: A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 8:613–621. 2001. View Article : Google Scholar : PubMed/NCBI
26	Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW and Korneluk RG: Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol. 3:128–133. 2001. View Article : Google Scholar : PubMed/NCBI
27	Ma TL, Ni PH, Zhong J, Tan JH, Qiao MM and Jiang SH: Low expression of XIAP-associated factor 1 in human colorectal cancers. Chin J Dig Dis. 6:10–14. 2005. View Article : Google Scholar : PubMed/NCBI
28	Lee MG, Huh JS, Chung SK, Lee JH, Byun DS, Ryu BK, Kang MJ, Chae KS, Lee SJ, Lee CH, et al: Promoter CpG hyper-methylation and downregulation of XAF1 expression in human urogenital malignancies: Implication for attenuated p53 response to apoptotic stresses. Oncogene. 25:5807–5822. 2006. View Article : Google Scholar : PubMed/NCBI
29	Chung SK, Lee MG, Ryu BK, Lee JH, Han J, Byun DS, Chae KS, Lee KY, Jang JY, Kim HJ, et al: Frequent alteration of XAF1 in human colorectal cancers: Implication for tumor cell resistance to apoptotic stresses. Gastroenterology. 132:2459–2477. 2007. View Article : Google Scholar : PubMed/NCBI
30	Chomczynski P and Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 162:156–159. 1987. View Article : Google Scholar : PubMed/NCBI
31	Ilyas M, Efstathiou JA, Straub J, Kim HC and Bodmer WF: Transforming growth factor beta stimulation of colorectal cancer cell lines: Type II receptor bypass and changes in adhesion molecule expression. Proc Natl Acad Sci USA. 96:3087–3091. 1999. View Article : Google Scholar : PubMed/NCBI
32	Wang X, Liu C, Wang J, Fan Y, Wang Z and Wang Y: Oxymatrine inhibits the migration of human colorectal carcinoma RKO cells via inhibition of PAI-1 and the TGF-β1/Smad signaling pathway. Oncol Rep. 37:747–753. 2017. View Article : Google Scholar
33	Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H and Grünert S: Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. J Cell Biol. 156:299–313. 2002. View Article : Google Scholar : PubMed/NCBI
34	Higgins SP, Samarakoon R, Higgins CE, Freytag J, Wilkins-Port CE and Higgins PJ: TGF-β1-induced expression of the anti-apoptotic PAI-1 protein requires EGFR signaling. Cell Commun Insights. 2:1–11. 2009. View Article : Google Scholar
35	Chen SC, Henry DO, Reczek PR and Wong MK: Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther. 7:1227–1236. 2008. View Article : Google Scholar : PubMed/NCBI
36	Byun DS, Cho K, Ryu BK, Lee MG, Kang MJ, Kim HR and Chi SG: Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas. Cancer Res. 63:7068–7075. 2003.PubMed/NCBI
37	Lee MG, Han J, Jeong SI, Her NG, Lee JH, Ha TK, Kang MJ, Ryu BK and Chi SG: XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. Proc Natl Acad Sci USA. 111:15532–15537. 2014. View Article : Google Scholar : PubMed/NCBI
38	Jeong SI, Kim JW, Ko KP, Ryu BK, Lee MG, Kim HJ and Chi SG: XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis. Cell Death Dis. 9:8062018. View Article : Google Scholar : PubMed/NCBI
39	Massagué J: How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 1:169–178. 2000. View Article : Google Scholar
40	McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar
41	Yu LF, Wang J, Zou B, Lin MC, Wu YL, Xia HH, Sun YW, Gu Q, He H, Lam SK, et al: XAF1 mediates apoptosis through an extracellular signal-regulated kinase pathway in colon cancer. Cancer. 109:1996–2003. 2007. View Article : Google Scholar : PubMed/NCBI
42	Levy L and Hill CS: Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 17:41–58. 2006. View Article : Google Scholar
43	Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, et al: Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 22:571–584. 2012. View Article : Google Scholar : PubMed/NCBI
44	Massagué J: TGFbeta in cancer. Cell. 134:215–230. 2008. View Article : Google Scholar : PubMed/NCBI
45	Jung B, Staudacher JJ and Beauchamp D: Transforming growth factor β superfamily signaling in development of colorectal cancer. Gastroenterology. 152:36–52. 2017. View Article : Google Scholar
46	Mao L, Li Y, Zhao J, Li Q, Yang B, Wang Y, Zhu Z, Sun H and Zhai Z: Transforming growth factor-β1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol Lett. 14:647–654. 2017. View Article : Google Scholar : PubMed/NCBI