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http://dx.doi.org/10.1038/s12276-018-0189-8

TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade  

Han, Zhezhu (Institute for Cancer Research, Yonsei University College of Medicine)
Kang, Dongxu (Institute for Cancer Research, Yonsei University College of Medicine)
Joo, Yeonsoo (Institute for Cancer Research, Yonsei University College of Medicine)
Lee, Jihyun (Institute for Cancer Research, Yonsei University College of Medicine)
Oh, Geun-Hyeok (Institute for Cancer Research, Yonsei University College of Medicine)
Choi, Soojin (Institute for Cancer Research, Yonsei University College of Medicine)
Ko, Suwan (Institute for Cancer Research, Yonsei University College of Medicine)
Je, Suyeon (Institute for Cancer Research, Yonsei University College of Medicine)
Choi, Hye Jin (Department of Internal Medicine, Yonsei University College of Medicine)
Song, Jae J. (Institute for Cancer Research, Yonsei University College of Medicine)
Publication Information
Experimental and Molecular Medicine / v.50, no.12, 2018 , pp. 4.1-4.19 More about this Journal
Abstract
Transforming growth factor $(TGF)-{\beta}$ signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, $TGF-{\beta}$ promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against $TGF-{\beta}1$ and $TGF-{\beta}2$ to investigate the role of $TGF-{\beta}$ downregulation in cancer cell death. We found that the downregulation of $TGF-{\beta}$ increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by $TGF-{\beta}$ downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type-specific manner. We also revealed the possibility of substantial gene fluctuation in response to $TGF-{\beta}$ downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress.
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1 Barranco-Medina, S., Lazaro, J. J. & Dietz, K. J. The oligomeric conformation of peroxiredoxins links redox state to function. FEBS Lett. 583, 1809-1816 (2009).   DOI
2 Ip, Y. T. & Davis, R. J. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development. Curr. Opin. Cell Biol. 10, 205-219 (1998).   DOI
3 Turjanski, A. G., Vaque, J. P. & Gutkind, J. S. MAP kinases and the control of nuclear events. Oncogene 26, 3240-3253 (2007).   DOI
4 Wagner, E. F. & Nebreda, A. R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 9, 537-549 (2009).   DOI
5 Guo, Y. L., Baysal, K., Kang, B., Yang, L. J. & Williamson, J. R. Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells. J. Biol. Chem. 273, 4027-4034 (1998).   DOI
6 Hartsough, M. T. & Mulder, K. M. Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J. Biol. Chem. 270, 7117-7124 (1995).   DOI
7 Engel,M. E., McDonnell, M. A., Law, B. K. & Moses, H. L. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J. Biol. Chem. 274, 37413-37420 (1999).   DOI
8 Begas, P., Liedgens, L., Moseler, A., Meyer, A. J. & Deponte, M. Glutaredoxin catalysis requires two distinct glutathione interaction sites. Nat. Commun. 8, 14835 (2017).   DOI
9 Friess, H. et al. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 53, 2704-2707 (1993).
10 Drabsch, Y. & ten Dijke, P. TGF-beta signalling and its role in cancer progression and metastasis. Cancer Metastas-. Rev. 31, 553-568 (2012).   DOI
11 Song, J. J. et al. Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2. J. Biol. Chem. 277, 46566-46575 (2002).   DOI
12 Rhee, S. G., Woo, H. A., Kil, I. S. & Bae, S. H. Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J. Biol. Chem. 287, 4403-4410 (2012).   DOI
13 Kim, J., Kang, D., Sun, B. K., Kim, J. H. & Song, J. J. TRAIL/MEKK4/p38/HSP27/Akt survival network is biphasically modulated by the Src/CIN85/c-Cbl complex. Cell. Signal. 25, 372-379 (2013).   DOI
14 Yu, L., Hebert, M. C. & Zhang, Y. E. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J. 21, 3749-3759 (2002).   DOI
15 Korpal, M. & Kang, Y. Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur. J. Cancer 46, 1232-1240 (2010).   DOI
16 Kang, D., Park, W., Lee, S., Kim, J. H. & Song, J. J. Crosstalk from survival to necrotic death coexists in DU-145 cells by curcumin treatment. Cell. Signal. 25, 1288-1300 (2013).   DOI
17 Hanafusa, H. et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J. Biol. Chem. 274, 27161-27167 (1999).   DOI
18 Yoo, Y. A., Kim, Y. H., Kim, J. S. & Seo, J. H. The functional implications of Akt activity and TGF-beta signaling in tamoxifen-resistant breast cancer. Biochim. Biophys. Acta 1783, 438-447 (2008).   DOI
19 Hernanda, P. Y. et al. SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma. Oncogene 34, 5055-5068 (2015).   DOI
20 Zhao, Y. et al. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Mol. Cancer 16, 79 (2017).   DOI
21 Roulston, A., Reinhard, C., Amiri, P. & Williams, L. T. Early activation of c-Jun Nterminal kinase and p38 kinase regulate cell survival in response to tumor necrosis factor alpha. J. Biol. Chem. 273, 10232-10239 (1998).   DOI
22 Zhang, J. et al. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell Longev. 2016, 4350965 (2016).
23 Syed, V. TGF-beta signaling in cancer. J. Cell. Biochem. 117, 1279-1287 (2016).   DOI
24 Mu, Y., Gudey, S. K. & Landstrom, M. Non-Smad signaling pathways. Cell Tissue Res. 347, 11-20 (2012).   DOI
25 Ichijo, H. et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90-94 (1997).   DOI
26 Chen, Z. et al. ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene 18, 173-180 (1999).   DOI
27 Kim, J. et al. HSP27 modulates survival signaling networks in cells treated with curcumin and TRAIL. Cell. Signal. 24, 1444-1452 (2012).   DOI
28 Hsieh, C. C. & Papaconstantinou, J. Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J. 20, 259-268 (2006).   DOI
29 Zhang, Y. E. Non-Smad pathways in TGF-beta signaling. Cell Res. 19, 128-139 (2009).   DOI
30 Matsukawa, J., Matsuzawa, A., Takeda, K. & Ichijo, H. The ASK1-MAP kinase cascades in mammalian stress response. J. Biochem. 136, 261-265 (2004).   DOI
31 Tobiume, K. et al. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2, 222-228 (2001).   DOI
32 Hayyan, M., Hashim, M. A. & AlNashef, I. M. Superoxide ion: generation and chemical implications. Chem. Rev. 116, 3029-3085 (2016).   DOI
33 Siegel, P. M. & Massague, J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat. Rev. Cancer 3, 807-821 (2003).   DOI
34 Muller, F. The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging. J. Am. Aging Assoc. 23, 227-253 (2000).
35 Papageorgis, P. TGFbeta signaling in tumor initiation, epithelial-tomesenchymal transition, and metastasis. J. Oncol. 2015, 587193 (2015).
36 Massague, J. TGF-beta signal transduction. Annu. Rev. Biochem. 67, 753-791 (1998).   DOI
37 Lebrun, J. J. The dual role of TGFbeta in human cancer: from tumor suppression to cancer metastasis. ISRN Mol. Biol. 2012, 381428 (2012).
38 Wakefield, L. M. & Hill, C. S. Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat. Rev. Cancer 13, 328-341 (2013).   DOI
39 Xu, J., Lamouille, S. & Derynck, R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19, 156-172 (2009).   DOI
40 Dumont, N. & Arteaga, C. L. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 3, 531-536 (2003).   DOI
41 Derynck, R., Akhurst, R. J. & Balmain, A. TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 29, 117-129 (2001).   DOI
42 Jakowlew, S. B. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 25, 435-457 (2006).   DOI
43 Malhotra, J. D. & Kaufman, R. J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9, 2277-2293 (2007).   DOI
44 Liou, G. Y. & Storz, P. Reactive oxygen species in cancer. Free Radic. Res. 44, 479-496 (2010).   DOI
45 Burdon, R. H., Gill, V. & Rice-Evans, C. Oxidative stress and tumour cell proliferation. Free Radic. Res. Commun. 11, 65-76 (1990).   DOI
46 Qu, K. et al. Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction. Acta Pharmacol. Sin. 34, 1217-1228 (2013).   DOI
47 Zeeshan, H. M., Lee, G. H., Kim, H. R. & Chae, H. J. Endoplasmic reticulum stress and associated ROS. Int. J. Mol. Sci. 17, 327 (2016).   DOI
48 Hetz, C., Martinon, F., Rodriguez, D. & Glimcher, L. H. The unfolded protein response: integrating stress signals through the stress sensor IRE1alpha. Physiol. Rev. 91, 1219-1243 (2011).   DOI
49 Powis, G., Mustacich, D. & Coon, A. The role of the redox protein thioredoxin in cell growth and cancer. Free Radic. Biol. Med. 29, 312-322 (2000).   DOI
50 Neuzillet, C. et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol. Ther. 147, 22-31 (2015).   DOI
51 Massague, J. TGFbeta signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616-630 (2012).   DOI
52 Wakefield, L. M. & Roberts, A. B. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr. Opin. Genet. Dev. 12, 22-29 (2002).   DOI
53 Massague, J. TGFbeta in cancer. Cell 134, 215-230 (2008).   DOI
54 Oh, S. et al. Transforming growth factor-beta gene silencing using adenovirus expressing TGF-beta1 or TGF-beta2 shRNA. Cancer Gene. Ther. 20, 94-100 (2013).   DOI
55 Saitoh, M. et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596-2606 (1998).   DOI
56 Fujino, G., Noguchi, T., Takeda, K. & Ichijo, H. Thioredoxin and protein kinases in redox signaling. Semin. Cancer Biol. 16, 427-435 (2006).   DOI
57 Cho, S. G. et al. Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J. Biol. Chem. 276, 12749-12755 (2001).   DOI
58 Ross, S. & Hill, C. S. How the Smads regulate transcription. Int. J. Biochem. Cell Biol. 40, 383-408 (2008).   DOI
59 Inman, G. J. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr. Opin. Genet. Dev. 21, 93-99 (2011).   DOI
60 Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425, 577-584 (2003).   DOI
61 Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783-2810 (2005).   DOI
62 Jaffe, A. B. & Hall, A. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247-269 (2005).   DOI
63 Son, Y. et al. Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways? J. Signal Transduct. 2011, 792639 (2011).
64 Pardali, K. & Moustakas, A. Actions of TGF-beta as tumor suppressor and prometastatic factor in human cancer. Biochim. Biophys. Acta 1775, 21-62 (2007).
65 Son, Y., Kim, S., Chung, H. T. & Pae, H. O. Reactive oxygen species in the activation of MAP kinases. Methods Enzymol. 528, 27-48 (2013).
66 McCubrey, J. A., Lahair, M. M. & Franklin, R. A. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid. Redox Signal. 8, 1775-1789 (2006).   DOI
67 Zafarullah, M., Li, W. Q., Sylvester, J. & Ahmad, M. Molecular mechanisms of Nacetylcysteine actions. Cell. Mol. Life Sci. 60, 6-20 (2003).   DOI
68 Huang, F. & Chen, Y. G. Regulation of TGF-beta receptor activity. Cell Biosci. 2, 9 (2012).   DOI
69 Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L. & Arteaga, C. L. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem. 275, 36803-36810 (2000).   DOI
70 Shin, I., Bakin, A. V., Rodeck, U., Brunet, A. & Arteaga, C. L. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol. Biol. Cell 12, 3328-3339 (2001).   DOI
71 Wang, S. E. The functional crosstalk between HER2 tyrosine kinase and TGFbeta signaling in breast cancer malignancy. J. Signal Transduct. 2011, 804236 (2011).
72 Yamaguchi, K. et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270, 2008-2011 (1995).   DOI
73 Kim, S. I., Kwak, J. H., Wang, L. & Choi, M. E. Protein phosphatase 2A is a negative regulator of transforming growth factor-beta1-induced TAK1 activation in mesangial cells. J. Biol. Chem. 283, 10753-10763 (2008).   DOI
74 Tuzun, S., Yucel, A. F., Pergel, A., Kemik, A. S. & Kemik, O. Lipid peroxidation and transforming growth factor-beta1 levels in gastric cancer at pathologic stages. Balk. Med. J. 29, 273-276 (2012).
75 Santos, C. X., Tanaka, L. Y., Wosniak, J. & Laurindo, F. R. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid. Redox Signal. 11, 2409-2427 (2009).   DOI
76 Galan, M. et al. Mechanism of endoplasmic reticulum stress-induced vascular endothelial dysfunction. Biochim. Biophys. Acta 1843, 1063-1075 (2014).   DOI
77 Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471 (1997).   DOI
78 Dropmann, A. et al. TGF-beta1 and TGF-beta2 abundance in liver diseases of mice and men. Oncotarget 7, 19499-19518 (2016).