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Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

Oncogene volume 28, pages 1982–1992 (2009)Cite this article

Abstract

Mammalian Stanniocalcin-1 (STC1) is a glycoprotein that has been implicated in various biological processes including angiogenesis. Aberrant STC1 expression has been reported in breast, ovarian and prostate cancers, but the significance of this is not well understood. Here, we report that oxidative stress caused a 40-fold increase in STC1 levels in mouse embryo fibroblasts (MEFs). STC1−/− MEFs were resistant to growth inhibition and cell death induced by H2O2 or by 20% O2 (which is hyperoxic for most mammalian cells); this is the first phenotype reported for STC1-null cells. STC1−/− cells had higher levels of activated MEK and ERK1/2 than their wild-type (WT) counterparts, and these levels were all reduced by stable expression of exogenous STC1 in STC1−/− cells. Furthermore, pharmacological inhibition by PD98059 or UO126 of MEK and therefore of ERK1/2 activation restored sensitivity of STC1−/− cells to oxidative stress. We also found that H2O2-induced STC1 expression in WT cells was abolished by inhibition of ERK1/2 activation. Thus, the ERK1/2 signaling pathway upregulates STC1 expression, which in turn downregulates the level of activated MEK and consequently ERK1/2 in a novel negative feedback loop. Therefore, STC1 expression downregulates prosurvival ERK1/2 signaling and reduces survival under conditions of oxidative stress.

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References

  • Adayev T, Ray I, Sondhi R, Sobocki T, Banerjee P . (2003). The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Calpha. Biochim Biophys Acta 1640: 85–96.

    Article  CAS  Google Scholar 

  • Arrington ED, Caldwell MC, Kumaravel TS, Lohani A, Joshi A, Evans MK et al. (2000). Enhanced sensitivity and long-term G2 arrest in hydrogen peroxide-treated Ku80-null cells are unrelated to DNA repair defects. Free Radic Biol Med 29: 1166–1176.

    Article  CAS  Google Scholar 

  • Bai XC, Deng F, Liu AL, Zou ZP, Wang Y, Ke ZY et al. (2002). Phospholipase C-gamma1 is required for cell survival in oxidative stress by protein kinase C. Biochem J 363: 395–401.

    Article  CAS  Google Scholar 

  • Bell SE, Mavila A, Salazar R, Bayless KJ, Kanagala S, Maxwell SA et al. (2001). Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J Cell Sci 114: 2755–2773.

    CAS  Google Scholar 

  • Benn SC, Woolf CJ . (2004). Adult neuron survival strategies—slamming on the brakes. Nat Rev Neurosci 5: 686–700.

    Article  CAS  Google Scholar 

  • Besser D, Presta M, Nagamine Y . (1995). Elucidation of a signaling pathway induced by FGF-2 leading to uPA gene expression in NIH 3T3 fibroblasts. Cell Growth Differ 6: 1009–1017.

    CAS  Google Scholar 

  • Bouras T, Southey MC, Chang AC, Reddel RR, Willhite D, Glynne R et al. (2002). Stanniocalcin 2 is an estrogen-responsive gene coexpressed with the estrogen receptor in human breast cancer. Cancer Res 62: 1289–1295.

    CAS  Google Scholar 

  • Chang AC, Cha J, Koentgen F, Reddel RR . (2005). The murine stanniocalcin 1 gene is not essential for growth and development. Mol Cell Biol 25: 10604–10610.

    Article  CAS  Google Scholar 

  • Chang AC, Dunham MA, Jeffrey KJ, Reddel RR . (1996). Molecular cloning and characterization of mouse stanniocalcin cDNA. Mol Cell Endocrinol 124: 185–187.

    Article  CAS  Google Scholar 

  • Chang ACM, Janosi J, Hulsbeek M, De Jong D, Jeffrey KJ, Noble JR et al. (1995). A novel human cDNA highly homologous to the fish hormone stanniocalcin. Mol Cell Endocrinol 112: 241–247.

    Article  CAS  Google Scholar 

  • Chang ACM, Jellinek DA, Reddel RR . (2003). Mammalian stanniocalcins and cancer. Endocr Relat Cancer 10: 359–373.

    Article  CAS  Google Scholar 

  • Di Micco R, Cicalese A, Fumagalli M, Dobreva M, Verrecchia A, Pelicci PG et al. (2008). DNA damage response activation in mouse embryonic fibroblasts undergoing replicative senescence and following spontaneous immortalization. Cell Cycle 22: 3601–3606.

    Article  Google Scholar 

  • Ellard JP, McCudden CR, Tanega C, James KA, Ratkovic S, Staples JF et al. (2007). The respiratory effects of stanniocalcin-1 (STC-1) on intact mitochondria and cells: STC-1 uncouples oxidative phosphorylation and its actions are modulated by nucleotide triphosphates. Mol Cell Endocrinol 264: 90–101.

    Article  CAS  Google Scholar 

  • Filvaroff EH, Guillet S, Zlot C, Bao M, Ingle G, Steinmetz H et al. (2002). Stanniocalcin 1 alters muscle and bone structure and function in transgenic mice. Endocrinology 143: 3681–3690.

    Article  CAS  Google Scholar 

  • Finkel T . (1998). Oxygen radicals and signaling. Curr Opin Cell Biol 10: 248–253.

    Article  CAS  Google Scholar 

  • Fujiwara Y, Sugita Y, Nakamori S, Miyamoto A, Shiozaki K, Nagano H et al. (2000). Assessment of stanniocalcin-1 mRNA as a molecular marker for micrometastases of various human cancers. Int J Oncol 16: 799–804.

    CAS  Google Scholar 

  • Ismail RS, Baldwin RL, Fang J, Browning D, Karlan BY, Gasson JC et al. (2000). Differential gene expression between normal and tumor-derived ovarian epithelial cells. Cancer Res 60: 6744–6749.

    CAS  Google Scholar 

  • Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JC et al. (1999). The transcriptional program in the response of human fibroblasts to serum. Science 283: 83–87.

    Article  CAS  Google Scholar 

  • Jellinek DA, Chang AC, Larsen MR, Wang X, Robinson PJ, Reddel RR . (2000). Stanniocalcin 1 and 2 are secreted as phosphoproteins from human fibrosarcoma cells. Biochem J 350: 453–461.

    Article  CAS  Google Scholar 

  • Jiang WQ, Chang ACM, Satoh M, Furuichi Y, Tam PP, Reddel RR . (2000). The distribution of stanniocalcin 1 protein in fetal mouse tissues suggests a role in bone and muscle development. J Endocrinol 165: 457–466.

    Article  CAS  Google Scholar 

  • Joensuu K, Heikkila P, Andersson LC . (2008). Tumor dormancy: elevated expression of stanniocalcins in late relapsing breast cancer. Cancer Lett 265: 76–83.

    Article  CAS  Google Scholar 

  • Kahn J, Mehraban F, Ingle G, Xin X, Bryant JE, Vehar G et al. (2000). Gene expression profiling in an in vitro model of angiogenesis. Am J Pathol 156: 1887–1900.

    Article  CAS  Google Scholar 

  • Kanellis J, Bick R, Garcia G, Truong L, Tsao CC, Etemadmoghadam D et al. (2003). Stanniocalcin-1, an inhibitor of macrophage chemotaxis and chemokinesis. Am J Physiol Renal Physiol 286: F356–F362.

    Article  Google Scholar 

  • Koizumi K, Hoshiai M, Ishida H, Ohyama K, Sugiyama H, Naito A et al. (2007). Stanniocalcin 1 prevents cytosolic Ca(2+) overload and cell hypercontracture in cardiomyocytes. Circ J 71: 796–801.

    Article  CAS  Google Scholar 

  • Lai KP, Law AY, Yeung HY, Lee LS, Wagner GF, Wong CK . (2007). Induction of stanniocalcin-1 expression in apoptotic human nasopharyngeal cancer cells by p53. Biochem Biophys Res Commun 356: 968–975.

    Article  CAS  Google Scholar 

  • Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL et al. (2001). Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 93: 1337–1343.

    Article  CAS  Google Scholar 

  • Lee IH, Lim HJ, Yoon S, Seong JK, Bae DS, Rhee SG et al. (2008). Ahnak protein activates protein kinase C (PKC) through dissociation of the PKC-protein phosphatase 2A complex. J Biol Chem 283: 6312–6320.

    Article  CAS  Google Scholar 

  • Long H, Han H, Yang B, Wang Z . (2003). Opposite cell density-dependence between spontaneous and oxidative stress-induced apoptosis in mouse fibroblast L-cells. Cell Physiol Biochem 13: 401–414.

    Article  CAS  Google Scholar 

  • Madsen KL, Tavernini MM, Yachimec C, Mendrick DL, Alfonso PJ, Buergin M et al. (1998). Stanniocalcin: a novel protein regulating calcium and phosphate transport across mammalian intestine. Am J Physiol 274: G96–G102.

    CAS  Google Scholar 

  • McCudden CR, James KA, Hasilo C, Wagner GF . (2002). Characterization of mammalian stanniocalcin receptors: mitochondrial targeting of ligand and receptor for regulation of cellular metabolism. J Biol Chem 277: 45249–45258.

    Article  CAS  Google Scholar 

  • Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y et al. (2001). Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 61: 2129–2137.

    CAS  Google Scholar 

  • Olsen HS, Cepeda MA, Zhang QQ, Rosen CA, Vozzolo BL, Wagner GF . (1996). Human stanniocalcin: a possible hormonal regulator of mineral metabolism. Proc Natl Acad Sci USA 93: 1792–1796.

    Article  CAS  Google Scholar 

  • Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J . (2003). Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5: 741–747.

    Article  CAS  Google Scholar 

  • Sheikh-Hamad D, Rouse D, Yang Y . (2000). Regulation of stanniocalcin in MDCK cells by hypertonicity and extracellular calcium. Am J Physiol 278: F417–F424.

    Article  CAS  Google Scholar 

  • Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T . (1995). Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270: 296–299.

    Article  CAS  Google Scholar 

  • Sundell K, Bjornsson BT, Itoh H, Kawauchi H . (1992). Chum salmon (Oncorhynchus keta) stanniocalcin inhibits in vitro calcium uptake in Atlantic cod (Gadus morhua). J Comp Physiol B 162: 489–495.

    Article  CAS  Google Scholar 

  • Todaro GJ, Green H . (1963). Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol 17: 299–313.

    Article  CAS  Google Scholar 

  • Vanderkooi JM, Erecinska M, Silver IA . (1991). Oxygen in mammalian tissue: methods of measurement and affinities of various reactions. Am J Physiol 260: C1131–C1150.

    Article  CAS  Google Scholar 

  • Varghese R, Gagliardi AD, Bialek PE, Yee SP, Wagner GF, DiMattia GE . (2002). Overexpression of human stanniocalcin affects growth and reproduction in transgenic mice. Endocrinology 143: 868–876.

    Article  CAS  Google Scholar 

  • Wagner GF, Fenwick JC, Park CM, Milliken C, Copp DH, Friesen HG . (1988). Comparative biochemistry and physiology of teleocalcin from sockeye and coho salmon. Gen Comp Endocrinol 72: 237–246.

    Article  CAS  Google Scholar 

  • Wagner GF, Vozzolo BL, Jaworski E, Haddad M, Kline RL, Olsen HS et al. (1997). Human stanniocalcin inhibits renal phosphate excretion in the rat. J Bone Miner Res 12: 165–171.

    Article  CAS  Google Scholar 

  • Wang X, Martindale JL, Liu Y, Holbrook NJ . (1998). The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J 333 (Pt 2): 291–300.

    Article  CAS  Google Scholar 

  • Welcsh PL, Lee MK, Gonzalez-Hernandez RM, Black DJ, Mahadevappa M, Swisher EM et al. (2002). BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Proc Natl Acad Sci USA 99: 7560–7565.

    Article  CAS  Google Scholar 

  • Westberg JA, Serlachius M, Lankila P, Andersson LC . (2007a). Hypoxic preconditioning induces elevated expression of stanniocalcin-1 in the heart. Am J Physiol Heart Circ Physiol 293: H1766–H1771.

    Article  CAS  Google Scholar 

  • Westberg JA, Serlachius M, Lankila P, Penkowa M, Hidalgo J, Andersson LC . (2007b). Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling. Stroke 38: 1025–1030.

    Article  CAS  Google Scholar 

  • Wu S, Yoshiko Y, De Luca F . (2006). Stanniocalcin 1 acts as a paracrine regulator of growth plate chondrogenesis. J Biol Chem 281: 5120–5127.

    Article  CAS  Google Scholar 

  • Xu J . (2005). Preparation, culture, and immortalization of mouse embryonic fibroblasts. In: Ausubel FM (ed). Current Protocols in Molecular Biology. John Wiley and Sons, Inc.: USA, Chapter 28, Unit 28.1.

    Google Scholar 

  • Yeung HY, Chan DK, Mak NK, Wagner GF, Wong CK . (2003). Identification of signal transduction pathways that modulate dibutyryl cyclic adenosine monophosphate activation of stanniocalcin gene expression in neuroblastoma cells. Endocrinology 144: 4446–4452.

    Article  CAS  Google Scholar 

  • Yeung HY, Lai KP, Chan HY, Mak NK, Wagner GF, Wong CK . (2005). Hypoxia-inducible factor-1-mediated activation of stanniocalcin-1 in human cancer cells. Endocrinology 146: 4951–4960.

    Article  CAS  Google Scholar 

  • Yoshiko Y, Maeda N, Aubin JE . (2003). Stanniocalcin 1 stimulates osteoblast differentiation in rat calvaria cell cultures. Endocrinology 144: 4134–4143.

    Article  CAS  Google Scholar 

  • Zhang K, Lindsberg PJ, Tatlisumak T, Kaste M, Olsen HS, Andersson LC . (2000). Stanniocalcin: a molecular guard of neurons during cerebral ischemia. Proc Natl Acad Sci USA 97: 3637–3642.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by an Australian Postgraduate Award, the Carcinogenesis Fellowship of the Cancer Council NSW and a National Health and Medical Research Council of Australia Senior Principal Research Fellowship.

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Authors and Affiliations

  1. Cancer Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia

    A Nguyen, A C M Chang & R R Reddel

  2. Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

    A Nguyen, A C M Chang & R R Reddel

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  1. A Nguyen
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Correspondence to R R Reddel.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Nguyen, A., Chang, A. & Reddel, R. Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress. Oncogene 28, 1982–1992 (2009). https://doi.org/10.1038/onc.2009.65

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