Advertisement

Endocrine

pp 1–12 | Cite as

Effects of low extracellular sodium on proliferation and invasive activity of cancer cells in vitro

  • Giada Marroncini
  • Benedetta Fibbi
  • Alice Errico
  • Cecilia Grappone
  • Mario Maggi
  • Alessandro PeriEmail author
Original Article

Abstract

Purpose

Hyponatremia is the most common electrolyte disorder in hospitalized patients, and its etiopathogenesis is related to an underlying tumor in 14% of cases. Hyponatremia has been associated with a worse outcome in several pathologies, including cancer, in which the leading cause of this electrolyte alteration is the syndrome of inappropriate antidiuresis. The aim of this study was to analyze in vitro the effects of low extracellular [Na+] in cancer progression.

Materials and methods

We used a previously validated experimental model of chronic hyponatremia to characterize the effects of low extracellular [Na+] in different human cancer cell lines: pancreatic adenocarcinoma (PANC-1), neuroblastoma (SK-N-AS, SH-SY5Y), colorectal adenocarcinoma (HCT-8), chronic myeloid leukemia (K562).

Results

Our results demonstrate a direct relationship between low [Na+], reduced cell adhesion and increased invasion and proliferation in all cell lines tested. Accordingly, the number of tumor colonies grown in soft agar and the expression of collagenases type IV (metalloproteinases 2 and 9) were markedly higher in cancer cells exposed to reduced extracellular [Na+]. Gene analysis showed an upregulation of molecular pathways involved in oxidative stress (heme oxygenase 1) and in proliferation and invasion (RhoA, ROCK-1, ROCK-2). The activation of RhoA/ROCK pathway was paralleled by a deregulation of the cytoskeleton-associated proteins, resulting in the promotion of actin cytoskeletal remodeling and cell invasion.

Conclusions

Overall, our data demonstrate for the first time that low [Na+] promotes cancer progression in vitro, thus suggesting that hyponatremia is not a simple bystander of disease severity in cancer.

Keywords

Low sodium [Na+Tumor invasion Human cancer cells Gene expression Carcinogenesis 

Notes

Acknowledgements

This research was supported by grants from Otsuka Pharmaceutical Europe Ltd., Accademia Nazionale di Medicina, PRIN 2017R5ZE2C.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12020_2019_2135_MOESM1_ESM.pptx (3.2 mb)
Supplementary Information.

References

  1. 1.
    H.J. Adrogue, N.E. Madias, Hyponatremia. New Engl. J. Med. 343, 888–888 (2000)CrossRefGoogle Scholar
  2. 2.
    A. Greenberg et al., Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney Int. 88, 167–177 (2015)PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    D. Wang et al., Rapid-onset hyponatremia and delirium following duloxetine treatment for postherpetic neuralgia: Case report and literature review. Med. (Baltim.) 97, e13178 (2018)CrossRefGoogle Scholar
  4. 4.
    A.L. Negri, J.C. Ayus, Hyponatremia and bone disease. Rev. Endocr. Metab. Disord. 18, 67–78 (2017)PubMedCrossRefGoogle Scholar
  5. 5.
    B. Fibbi et al., Low extracellular sodium promotes adipogenic commitment of human mesenchymal stromal cells: a novel mechanism for chronic hyponatremia-induced bone loss. Endocrine 52, 73–85 (2016)PubMedCrossRefGoogle Scholar
  6. 6.
    R. Wald, B.L. Jaber, L.L. Price, A. Upadhyay, N.E. Madias, Impact of hospital-associated hyponatremia on selected outcomes. Arch. Intern. Med. 170, 294–302 (2010)PubMedCrossRefGoogle Scholar
  7. 7.
    G. Corona et al., Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS ONE 8, e80451 (2013)PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    S. Mohan, S. Gu, A. Parikh, J. Radhakrishnan, Prevalence of hyponatremia and association with mortality: results from NHANES. Am. J. Med. 126, 1127–1137 (2013)PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    A. Luca et al., An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis. Liver Transpl. 13, 1174–1180 (2007)PubMedCrossRefGoogle Scholar
  10. 10.
    J.L. Grodin, Pharmacologic approaches to electrolyte abnormalities in heart failure. Curr. Heart Fail Rep. 13, 181–189 (2016)PubMedCrossRefGoogle Scholar
  11. 11.
    J. Rossi et al., Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial. Acute Card. Care 9, 82–86 (2007)PubMedCrossRefGoogle Scholar
  12. 12.
    V. Nair, M.S. Niederman, N. Masani, S. Fishbane, Hyponatremia in community-acquired pneumonia. Am. J. Nephrol. 27, 184–190 (2007)PubMedCrossRefGoogle Scholar
  13. 13.
    J.J. Castillo, M. Vincent, E. Justice, Diagnosis and management of hyponatremia in cancer patients. Oncologist 17, 756–765 (2012)PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    A. Zogheri et al., Hyponatremia and pituitary adenoma: think twice about the etiopathogenesis. J. Endocrinol. Invest. 29, 750–753 (2006)PubMedCrossRefGoogle Scholar
  15. 15.
    R. Berardi et al., Practical issues for the management of hyponatremia in oncology. Endocrine 6, 158–164 (2018)CrossRefGoogle Scholar
  16. 16.
    P.L. Padfield et al., Plasma arginine vasopressin in the syndrome of antidiuretic hormone excess associated with bronchogenic carcinoma. Am. J. Med. 61, 825–831 (1976)PubMedCrossRefGoogle Scholar
  17. 17.
    J. Shapiro, G.E. Richardson, Hyponatremia of malignancy. Crit. Rev. Oncol. Hematol. 18, 129–135 (1995)PubMedCrossRefGoogle Scholar
  18. 18.
    J.B. Sorensen, M.K. Andersen, H.H. Hansen, Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J. Intern. Med. 238, 97–110 (1995)PubMedCrossRefGoogle Scholar
  19. 19.
    P. Gines, M. Guevara, Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology 48, 1002–1010 (2008)PubMedCrossRefGoogle Scholar
  20. 20.
    M. Cescon et al., Indication of the extent of hepatectomy for hepatocellular carcinoma on cirrhosis by a simple algorithm based on preoperative variables. Arch. Surg. 144, 57–63 (2009). discussion 63PubMedCrossRefGoogle Scholar
  21. 21.
    N.S. Vasudev et al., Prognostic factors in renal cell carcinoma: association of preoperative sodium concentration with survival. Clin. Cancer Res. 14, 1775–1781 (2008)PubMedCrossRefGoogle Scholar
  22. 22.
    F.A. Schutz et al., The impact of low serum sodium on treatment outcome of targeted therapy in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Cancer Database Consortium. Eur. Urol. 65, 723–730 (2014)PubMedCrossRefGoogle Scholar
  23. 23.
    M.H. Zhou et al., Clinical outcome of 30 patients with bone marrow metastases. J. Cancer Res Ther. 14, S512–S515 (2018)PubMedCrossRefGoogle Scholar
  24. 24.
    J.S. Choi, E.H. Bae, S.K. Ma, S.S. Kweon, S.W. Kim, Prognostic impact of hyponatraemia in patients with colorectal cancer. Colorectal Dis. 17, 409–416 (2015)PubMedCrossRefGoogle Scholar
  25. 25.
    H.S. Dhaliwal et al., Combination chemotherapy for intermediate and high grade non-Hodgkin's lymphoma. Br. J. Cancer 68, 767–774 (1993)PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    R. Berardi et al., Hyponatraemia is a predictor of clinical outcome for malignant pleural mesothelioma. Support Care Cancer 23, 621–626 (2015)PubMedCrossRefGoogle Scholar
  27. 27.
    L. Gandhi, B.E. Johnson, Paraneoplastic syndromes associated with small cell lung cancer. J. Natl. Compr. Canc Netw. 4, 631–638 (2006)PubMedCrossRefGoogle Scholar
  28. 28.
    N.S. Rawson, J. Peto, An overview of prognostic factors in small cell lung cancer. A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Br. J. Cancer 61, 597–604 (1990)PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    G. Corona et al., Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS ONE 10, e0124105 (2015)PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    K. Balachandran, A. Okines, R. Gunapala, D. Morganstein, S. Popat, Resolution of severe hyponatraemia is associated with improved survival in patients with cancer. BMC Cancer 15, 163 (2015)PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    C. Petereit, O. Zaba, I. Teber, C. Grohe, Is hyponatremia a prognostic marker of survival for lung cancer? Pneumologie 65, 565–571 (2011)PubMedCrossRefGoogle Scholar
  32. 32.
    P.M. Kasi, Proposing the use of hyponatremia as a marker to help identify high risk individuals for lung cancer. Med Hypotheses 79, 327–328 (2012)PubMedCrossRefGoogle Scholar
  33. 33.
    A.N. Jeppesen, H.K. Jensen, F. Donskov, N. Marcussen, H. von der Maase, Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma. Br. J. Cancer 102, 867–872 (2010)PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    P. Penttila, P. Bono, K. Peltola, F. Donskov, Hyponatremia associates with poor outcome in metastatic renal cell carcinoma patients treated with everolimus: prognostic impact. Acta Oncol. 57, 1580–1585 (2018)PubMedCrossRefGoogle Scholar
  35. 35.
    R. Berardi et al., Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy. Oncotarget 8, 23871–23879 (2017)PubMedCrossRefGoogle Scholar
  36. 36.
    A. Chawla, R.H. Sterns, S.U. Nigwekar, J.D. Cappuccio, Mortality and serum sodium: do patients die from or with hyponatremia? Clin. J. Am. Soc. Nephrol. 6, 960–965 (2011)PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    S.H. Kang et al., Is the sodium level per se related to mortality in hospitalized patients with severe hyponatremia? Clin. Nephrol. 77, 182–187 (2012)PubMedCrossRefGoogle Scholar
  38. 38.
    S. Benvenuti et al., Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia. Neuromol. Med. 15, 493–503 (2013)CrossRefGoogle Scholar
  39. 39.
    J. Barsony, Y. Sugimura, J.G. Verbalis, Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J. Biol. Chem. 286, 10864–10875 (2011)PubMedCrossRefGoogle Scholar
  40. 40.
    J. Shi, M. Surma, L. Zhang, L. Wei, Dissecting the roles of ROCK isoforms in stress-induced cell detachment. Cell Cycle 12, 1492–1500 (2013)PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    K. Tanaka et al., Structural basis for cofilin binding and actin filament disassembly. Nat. Commun. 9, 1860 (2018)PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    M. Arpin, D. Chirivino, A. Naba, I. Zwaenepoel, Emerging role for ERM proteins in cell adhesion and migration. Cell Adhes. Migr. 5, 199–206 (2011)CrossRefGoogle Scholar
  43. 43.
    M. Krause, E.W. Dent, J.E. Bear, J.J. Loureiro, F.B. Gertler, Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration. Annu. Rev. Cell Dev. Biol. 19, 541–564 (2003)PubMedCrossRefGoogle Scholar
  44. 44.
    H.Y. Yoo et al., A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 371–375 (2014)PubMedCrossRefGoogle Scholar
  45. 45.
    M. Sakata-Yanagimoto et al., Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014)PubMedCrossRefGoogle Scholar
  46. 46.
    C. Dyberg et al., Rho-associated kinase is a therapeutic target in neuroblastoma. Proc. Natl Acad. Sci. USA 114, E6603–E6612 (2017)PubMedCrossRefGoogle Scholar
  47. 47.
    M. Kakiuchi et al., Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat. Genet. 46, 583–587 (2014)PubMedCrossRefGoogle Scholar
  48. 48.
    L. Wei, M. Surma, S. Shi, N. Lambert-Cheatham, J. Shi, Novel insights into the roles of Rho kinase in cancer. Arch. Immunol. Ther. Exp. (Warsz.) 64, 259–278 (2016)CrossRefGoogle Scholar
  49. 49.
    K. Itoh et al., An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat. Med. 5, 221–225 (1999)PubMedCrossRefGoogle Scholar
  50. 50.
    V. Sanz-Moreno et al., ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20, 229–245 (2011)PubMedCrossRefGoogle Scholar
  51. 51.
    N. Rath et al., ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. EMBO Mol. Med. 9, 198–218 (2017)PubMedCrossRefGoogle Scholar
  52. 52.
    R. Squecco et al., Hyponatraemia alters the biophysical properties of neuronal cells independently of osmolarity: a study on Ni(2+) -sensitive current involvement. Exp. Physiol. 101, 1086–1100 (2016)PubMedCrossRefGoogle Scholar
  53. 53.
    D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)PubMedCrossRefGoogle Scholar
  54. 54.
    E. Panieri, M.M. Santoro, ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis. 7, e2253 (2016)PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    J. Zelenka, M. Koncosova, T. Ruml, Targeting of stress response pathways in the prevention and treatment of cancer. Biotechnol. Adv. 36, 583–602 (2018)PubMedCrossRefGoogle Scholar
  56. 56.
    L.J. Marnett, Oxyradicals and DNA damage. Carcinogenesis 21, 361–370 (2000)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pituitary Diseases and Sodium Alterations UnitAOU CareggiFlorenceItaly
  2. 2.Endocrinology, Department of Experimental and Clinical Biomedical Sciences ”Mario Serio”University of Florence, AOU CareggiFlorenceItaly
  3. 3.Gastroenterology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”University of Florence, AOU CareggiFlorenceItaly

Personalised recommendations