Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Biphasic Regulation of Mitogen-Activated Protein Kinase Phosphatase 3 in Hypoxic Colon Cancer Cells

  • Kim, Hong Seok (Department of Molecular Medicine, College of Medicine, Inha University) ;
  • Kang, Yun Hee (Eulji Biomedical Science Research Institute, Eulji University School of Medicine) ;
  • Lee, Jisu (Department of Microbiology and Immunology, Eulji University School of Medicine) ;
  • Han, Seung Ro (Eulji Biomedical Science Research Institute, Eulji University School of Medicine) ;
  • Kim, Da Bin (Department of Molecular Medicine, College of Medicine, Inha University) ;
  • Ko, Haeun (Medical Course, College of Medicine, Inha University) ;
  • Park, Seyoun (Medical Course, College of Medicine, Inha University) ;
  • Lee, Myung-Shin (Department of Microbiology and Immunology, Eulji University School of Medicine)
  • Received : 2021.04.07
  • Accepted : 2021.08.20
  • Published : 2021.10.31
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Abstract

Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment.

Keywords

Acknowledgement

The present study was supported by a grant to H.S.K. from the National Research Foundation of Korea (NRF) grants (NRF-2018R1D1A1B07040397).

References

  1. Arkell, R.S., Dickinson, R.J., Squires, M., Hayat, S., Keyse, S.M., and Cook, S.J. (2008). DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5. Cell. Signal. 20, 836-843. https://doi.org/10.1016/j.cellsig.2007.12.014
  2. Azimi, I., Petersen, R.M., Thompson, E.W., Roberts-Thomson, S.J., and Monteith, G.R. (2017). Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells. Sci. Rep. 7, 15140. https://doi.org/10.1038/s41598-017-15474-7
  3. Beasley, N.J., Wykoff, C.C., Watson, P.H., Leek, R., Turley, H., Gatter, K., Pastorek, J., Cox, G.J., Ratcliffe, P., and Harris, A.L. (2001). Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. Cancer Res. 61, 5262-5267.
  4. Beaudry, K., Langlois, M.J., Montagne, A., Cagnol, S., Carrier, J.C., and Rivard, N. (2019). Dual-specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis. J. Cell. Physiol. 234, 6731-6745. https://doi.org/10.1002/jcp.27420
  5. Bermudez, O., Jouandin, P., Rottier, J., Bourcier, C., Pages, G., and Gimond, C. (2011). Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia. J. Cell. Physiol. 226, 276-284. https://doi.org/10.1002/jcp.22339
  6. Bloethner, S., Chen, B., Hemminki, K., Muller-Berghaus, J., Ugurel, S., Schadendorf, D., and Kumar, R. (2005). Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis 26, 1224-1232. https://doi.org/10.1093/carcin/bgi066
  7. Byun, Y., Choi, Y.C., Jeong, Y., Yoon, J., and Baek, K. (2020). Long noncoding RNA expression profiling reveals upregulation of uroplakin 1A and uroplakin 1A antisense RNA 1 under hypoxic conditions in lung cancer cells. Mol. Cells 43, 975-988. https://doi.org/10.14348/molcells.2020.0126
  8. Camps, M., Nichols, A., and Arkinstall, S. (2000). Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 14, 6-16. https://doi.org/10.1096/fasebj.14.1.6
  9. Caunt, C.J. and Keyse, S.M. (2013). Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 280, 489-504. https://doi.org/10.1111/j.1742-4658.2012.08716.x
  10. Chan, D.W., Liu, V.W., Tsao, G.S., Yao, K.M., Furukawa, T., Chan, K.K., and Ngan, H.Y. (2008). Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis 29, 1742-1750. https://doi.org/10.1093/carcin/bgn167
  11. Chan, G., Gu, S., and Neel, B.G. (2013). Erk1 and Erk2 are required for maintenance of hematopoietic stem cells and adult hematopoiesis. Blood 121, 3594-3598. https://doi.org/10.1182/blood-2012-12-476200
  12. Chang, L. and Karin, M. (2001). Mammalian MAP kinase signalling cascades. Nature 410, 37-40. https://doi.org/10.1038/35065000
  13. Comerford, K.M., Cummins, E.P., and Taylor, C.T. (2004). c-Jun NH2-terminal kinase activation contributes to hypoxia-inducible factor 1alphadependent P-glycoprotein expression in hypoxia. Cancer Res. 64, 9057-9061. https://doi.org/10.1158/0008-5472.CAN-04-1919
  14. Croonquist, P.A., Linden, M.A., Zhao, F., and Van Ness, B.G. (2003). Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations, and coculture with bone marrow stromal cells. Blood 102, 2581-2592. https://doi.org/10.1182/blood-2003-04-1227
  15. Dhillon, A.S., Hagan, S., Rath, O., and Kolch, W. (2007). MAP kinase signalling pathways in cancer. Oncogene 26, 3279-3290. https://doi.org/10.1038/sj.onc.1210421
  16. Dhup, S., Dadhich, R.K., Porporato, P.E., and Sonveaux, P. (2012). Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr. Pharm. Des. 18, 1319-1330. https://doi.org/10.2174/138161212799504902
  17. Furukawa, T., Sunamura, M., Motoi, F., Matsuno, S., and Horii, A. (2003). Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am. J. Pathol. 162, 1807-1815. https://doi.org/10.1016/S0002-9440(10)64315-5
  18. Gkotinakou, I.M., Befani, C., Simos, G., and Liakos, P. (2019). ERK1/2 phosphorylates HIF-2alpha and regulates its activity by controlling its CRM1-dependent nuclear shuttling. J. Cell Sci. 132, jcs225698. https://doi.org/10.1242/jcs.225698
  19. Harris, A.L. (2002). Hypoxia--a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38-47. https://doi.org/10.1038/nrc704
  20. Hockel, M. and Vaupel, P. (2001). Biological consequences of tumor hypoxia. Semin. Oncol. 28(2 Suppl 8), 36-41. https://doi.org/10.1016/S0093-7754(01)90211-8
  21. Hsu, W.C., Chen, M.Y., Hsu, S.C., Huang, L.R., Kao, C.Y., Cheng, W.H., Pan, C.H., Wu, M.S., Yu, G.Y., Hung, M.S., et al. (2018). DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation. Proc. Natl. Acad. Sci. U. S. A. 115, E8027-E8036.
  22. Jurek, A., Amagasaki, K., Gembarska, A., Heldin, C.H., and Lennartsson, J. (2009). Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation. J. Biol. Chem. 284, 4626-4634. https://doi.org/10.1074/jbc.M808490200
  23. Keyse, S.M. (2000). Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr. Opin. Cell Biol. 12, 186-192. https://doi.org/10.1016/S0955-0674(99)00075-7
  24. Keyse, S.M. (2008). Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 27, 253-261. https://doi.org/10.1007/s10555-008-9123-1
  25. Kietzmann, T., Mennerich, D., and Dimova, E.Y. (2016). Hypoxia-inducible factors (HIFs) and phosphorylation: impact on stability, localization, and transactivity. Front. Cell Dev. Biol. 4, 11. https://doi.org/10.3389/fcell.2016.00011
  26. Koh, M.Y. and Powis, G. (2012). Passing the baton: the HIF switch. Trends Biochem. Sci. 37, 364-372. https://doi.org/10.1016/j.tibs.2012.06.004
  27. Li, C., Ma, H., Wang, Y., Cao, Z., Graves-Deal, R., Powell, A.E., Starchenko, A., Ayers, G.D., Washington, M.K., Kamath, V., et al. (2014). Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer. J. Clin. Invest. 124, 2172-2187. https://doi.org/10.1172/JCI71103
  28. Ma, J., Yu, X., Guo, L., and Lu, S.H. (2013). DUSP6, a tumor suppressor, is involved in differentiation and apoptosis in esophageal squamous cell carcinoma. Oncol. Lett. 6, 1624-1630. https://doi.org/10.3892/ol.2013.1605
  29. Manalo, D.J., Rowan, A., Lavoie, T., Natarajan, L., Kelly, B.D., Ye, S.Q., Garcia, J.G., and Semenza, G.L. (2005). Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659-669. https://doi.org/10.1182/blood-2004-07-2958
  30. Marchetti, S., Gimond, C., Chambard, J.C., Touboul, T., Roux, D., Pouyssegur, J., and Pages, G. (2005). Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Mol. Cell. Biol. 25, 854-864. https://doi.org/10.1128/MCB.25.2.854-864.2005
  31. Minet, E., Michel, G., Mottet, D., Raes, M., and Michiels, C. (2001). Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation. Free Radic. Biol. Med. 31, 847-855. https://doi.org/10.1016/S0891-5849(01)00657-8
  32. Mishra, O.P. and Delivoria-Papadopoulos, M. (2004). Effect of hypoxia on the expression and activity of mitogen-activated protein (MAP) kinasephosphatase-1 (MKP-1) and MKP-3 in neuronal nuclei of newborn piglets: the role of nitric oxide. Neuroscience 129, 665-673. https://doi.org/10.1016/j.neuroscience.2004.09.005
  33. Moncho-Amor, V., Pintado-Berninches, L., Ibanez de Caceres, I., Martin-Villar, E., Quintanilla, M., Chakravarty, P., Cortes-Sempere, M., FernandezVaras, B., Rodriguez-Antolin, C., de Castro, J., et al. (2019). Role of Dusp6 phosphatase as a tumor suppressor in non-small cell lung cancer. Int. J. Mol. Sci. 20, 2036. https://doi.org/10.3390/ijms20082036
  34. Mu, X., Shi, W., Xu, Y., Xu, C., Zhao, T., Geng, B., Yang, J., Pan, J., Hu, S., Zhang, C., et al. (2018). Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle 17, 428-438. https://doi.org/10.1080/15384101.2018.1444305
  35. Olive, P.L., Vikse, C., and Trotter, M.J. (1992). Measurement of oxygen diffusion distance in tumor cubes using a fluorescent hypoxia probe. Int. J. Radiat. Oncol. Biol. Phys. 22, 397-402. https://doi.org/10.1016/0360-3016(92)90840-e
  36. Ramnarain, D.B., Park, S., Lee, D.Y., Hatanpaa, K.J., Scoggin, S.O., Otu, H., Libermann, T.A., Raisanen, J.M., Ashfaq, R., Wong, E.T., et al. (2006). Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells. Cancer Res. 66, 867-874. https://doi.org/10.1158/0008-5472.CAN-05-2753
  37. Rankin, E.B. and Giaccia, A.J. (2008). The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15, 678-685. https://doi.org/10.1038/cdd.2008.21
  38. Richard, D.E., Berra, E., Gothie, E., Roux, D., and Pouyssegur, J. (1999). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF1. J. Biol. Chem. 274, 32631-32637. https://doi.org/10.1074/jbc.274.46.32631
  39. Semenza, G.L. (2010). Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625-634. https://doi.org/10.1038/onc.2009.441
  40. Semenza, G.L. (2012). Hypoxia-inducible factors in physiology and medicine. Cell 148, 399-408. https://doi.org/10.1016/j.cell.2012.01.021
  41. Shen, Z., Zhang, C., Qu, L., Lu, C., Xiao, M., Ni, R., and Liu, J. (2019). MKP-4 suppresses hepatocarcinogenesis by targeting ERK1/2 pathway. Cancer Cell Int. 19, 61. https://doi.org/10.1186/s12935-019-0776-3
  42. Shin, S.Y., Rath, O., Choo, S.M., Fee, F., McFerran, B., Kolch, W., and Cho, K.H. (2009). Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J. Cell Sci. 122, 425-435. https://doi.org/10.1242/jcs.036319
  43. Sodhi, A., Montaner, S., Miyazaki, H., and Gutkind, J.S. (2001). MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1alpha in rasV12 upregulation of VEGF. Biochem. Biophys. Res. Commun. 287, 292-300. https://doi.org/10.1006/bbrc.2001.5532
  44. Urosevic, J., Garcia-Albeniz, X., Planet, E., Real, S., Cespedes, M.V., Guiu, M., Fernandez, E., Bellmunt, A., Gawrzak, S., Pavlovic, M., et al. (2014). Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nat. Cell Biol. 16, 685-694. https://doi.org/10.1038/ncb2977
  45. Vaupel, P., Thews, O., and Hoeckel, M. (2001). Treatment resistance of solid tumors: role of hypoxia and anemia. Med. Oncol. 18, 243-259. https://doi.org/10.1385/MO:18:4:243
  46. Wagner, E.F. and Nebreda, A.R. (2009). Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 9, 537-549. https://doi.org/10.1038/nrc2694
  47. Waha, A., Felsberg, J., Hartmann, W., von dem Knesebeck, A., Mikeska, T., Joos, S., Wolter, M., Koch, A., Yan, P.S., Endl, E., et al. (2010). Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP2 relieves its growth suppressive activity in glioma cells. Cancer Res. 70, 1689-1699. https://doi.org/10.1158/0008-5472.CAN-09-3218
  48. Walenta, S. and Mueller-Klieser, W.F. (2004). Lactate: mirror and motor of tumor malignancy. Semin. Radiat. Oncol. 14, 267-274. https://doi.org/10.1016/j.semradonc.2004.04.004
  49. Warmka, J.K., Mauro, L.J., and Wattenberg, E.V. (2004). Mitogen-activated protein kinase phosphatase-3 is a tumor promoter target in initiated cells that express oncogenic Ras. J. Biol. Chem. 279, 33085-33092. https://doi.org/10.1074/jbc.M403120200
  50. Wenger, R.H., Stiehl, D.P., and Camenisch, G. (2005). Integration of oxygen signaling at the consensus HRE. Sci. STKE 2005, re12.
  51. Wong, V.C., Chen, H., Ko, J.M., Chan, K.W., Chan, Y.P., Law, S., Chua, D., Kwong, D.L., Lung, H.L., Srivastava, G., et al. (2012). Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype. Int. J. Cancer 130, 83-95. https://doi.org/10.1002/ijc.25970
  52. Xu, S., Furukawa, T., Kanai, N., Sunamura, M., and Horii, A. (2005). Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. J. Hum. Genet. 50, 159-167. https://doi.org/10.1007/s10038-005-0235-y
  53. Zhu, M.M., Tong, J.L., Xu, Q., Nie, F., Xu, X.T., Xiao, S.D., and Ran, Z.H. (2012). Increased JNK1 signaling pathway is responsible for ABCG2-mediated multidrug resistance in human colon cancer. PLoS One 7, e41763. https://doi.org/10.1371/journal.pone.0041763