Possible association of CAG repeat polymorphism in KCNN3 encoding the potassium channel SK3 with oxaliplatin-induced neurotoxicity

  • Benjamin Anon
  • Bérenger Largeau
  • Alban Girault
  • Aurélie Chantome
  • Morgane Caulet
  • Clémence Perray
  • Driffa Moussata
  • Christophe Vandier
  • Chantal Barin-Le Guellec
  • Thierry Lecomte
Original Article
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Abstract

Introduction

Data suggest a role of the potassium channel SK3 (KCNN3 gene) in oxaliplatin-induced neurotoxicity (OIN). Length variations in the polymorphic CAG repeat of the KCNN3 gene may be associated with the risk of OIN.

Materials and methods

We performed patch-clamp experiments on HEK293 cell lines, expressing SK3 channel isoforms with short (11) or long (24) CAG repetitions, to measure intracellular calcium concentrations to test the effects of oxaliplatin on current density. A retrospective study was carried out on patients with colorectal cancer who had received oxaliplatin-based chemotherapy. DNA for KCNN3 genotyping was extracted from leukocytes. The region containing the CAG repeats was amplified by PCR and the products separated by capillary electrophoresis for length analysis. The patients were divided into three groups depending on whether they carried two short alleles, one short allele and one long allele, or two long alleles. The primary endpoint was the onset of grade 2 or 3 neuropathy to oxaliplatin.

Results

There was no difference in current density, but oxaliplatin induced a differential effect on apamin-sensitive current density between the two isoforms expressed in the HEK cell lines. There was a significant reduction of store-operated calcium entry into cells expressing the short and more active isoform only after high concentration of oxaliplatin exposition. Eighty-six patients were included in the clinical study. There was no significant association between OIN and KCNN3 polymorphism for the three groups.

Conclusion

We observed a slight association between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model, but not a clinical study.

Keywords

Neuropathy Platinum KCNN3 SK3 channel Oxaliplatin 

Notes

Acknowledgements

The authors would like to thank Network “Ion channels and cancer—Canceropôle Grand Ouest”, (IC-CGO) France (http://www.ic-cgo.fr/). Prof. Dr. Luis A. Pardo (Max-Planck-Institute of Experimental Medicine, Germany) kindly gave us HEK cells expressing long and short SK3.

Funding

A. Girault had a fellowship from the “Fondation de France”.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

References

  1. 1.
    de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947CrossRefPubMedGoogle Scholar
  2. 2.
    Andre T, Boni C, Mounedji-Boudiaf L et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351CrossRefPubMedGoogle Scholar
  3. 3.
    Gamelin L, Boisdron-Celle M, Morel A et al (2006) Oxaliplatin neurotoxicity. Bull Cancer 93(Suppl 1):S17–S22Google Scholar
  4. 4.
    Ta LE, Espeset L, Podratz J et al (2006) Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding. Neurotoxicology 27:992–1002CrossRefPubMedGoogle Scholar
  5. 5.
    Di Cesare Mannelli L, Pacini A, Micheli L et al (2014) Glial role in oxaliplatin-induced neuropathic pain. Exp Neurol 261:22–33CrossRefPubMedGoogle Scholar
  6. 6.
    Park SB, Lin CS, Kiernan MC (2012) Nerve excitability assessment in chemotherapy-induced neurotoxicity. J Vis Exp.  https://doi.org/10.3791/3439 Google Scholar
  7. 7.
    Park SB, Lin CS-Y, Krishnan AV et al (2009) Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain 132:2712–2723CrossRefPubMedGoogle Scholar
  8. 8.
    Grolleau F, Gamelin L, Boisdron-Celle M et al (2001) A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 85:2293–2297CrossRefPubMedGoogle Scholar
  9. 9.
    Kagiava A, Tsingotjidou A, Emmanouilides C et al (2008) The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat. Neurotoxicology 29:1100–1106CrossRefPubMedGoogle Scholar
  10. 10.
    Sittl R, Carr RW, Fleckenstein J et al (2010) Enhancement of axonal potassium conductance reduces nerve hyperexcitability in an in vitro model of oxaliplatin-induced acute neuropathy. Neurotoxicology 31:694–700CrossRefPubMedGoogle Scholar
  11. 11.
    Descoeur J, Pereira V, Pizzoccaro A et al (2011) Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol Med 3:266–278CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Benoit E, Brienza S, Dubois JM (2006) Oxaliplatin, an anticancer agent that affects both Na+ and K+ channels in frog peripheral myelinated axons. Gen Physiol Biophys 25:263–276CrossRefPubMedGoogle Scholar
  13. 13.
    Wu S-N, Chen B-S, Wu Y-H et al (2009) The mechanism of the actions of oxaliplatin on ion currents and action potentials in differentiated NG108-15 neuronal cells. Neurotoxicology 30:677–685CrossRefPubMedGoogle Scholar
  14. 14.
    Stocker M, Pedarzani P (2000) Differential distribution of three Ca(2+)-activated K(+) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci 15:476–493CrossRefPubMedGoogle Scholar
  15. 15.
    Dilly S, Poncin S, Lamy C et al (2012) Physiology, pharmacology and modelling of potassium channels: focus on SK channels. Med Sci (Paris) 28:395–402CrossRefGoogle Scholar
  16. 16.
    Chandy KG, Fantino E, Wittekindt O et al (1998) Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Mol Psychiatry 3:32–37CrossRefPubMedGoogle Scholar
  17. 17.
    Figueroa KP, Chan P, Schöls L et al (2001) Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia. Arch Neurol 58:1649–1653CrossRefPubMedGoogle Scholar
  18. 18.
    Li T, Hu X, Chandy KG et al (1998) Transmission disequilibrium analysis of a triplet repeat within the hKCa3 gene using family trios with schizophrenia. Biochem Biophys Res Commun 251:662–665CrossRefPubMedGoogle Scholar
  19. 19.
    Grube S, Gerchen MF, Adamcio B et al (2011) A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. EMBO molecular medicine 3:309–319CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ritsner M, Modai I, Ziv H et al (2002) An association of CAG repeats at the KCNN3 locus with symptom dimensions of schizophrenia. Biol Psychiat 51:788–794CrossRefPubMedGoogle Scholar
  21. 21.
    Mössner R, Weichselbaum A, Marziniak M et al (2005) A highly polymorphic poly-glutamine stretch in the potassium channel KCNN3 in migraine. Headache 45:132–136CrossRefPubMedGoogle Scholar
  22. 22.
    Basso M, Modoni A, Spada D et al (2011) Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity. Cancer Chemother Pharmacol 67:1179–1187CrossRefPubMedGoogle Scholar
  23. 23.
    Park SB, Lin CS-Y, Krishnan AV et al (2011) The contribution of SK3 polymorphisms to acute oxaliplatin-induced neurotoxicity: direct or indirect effects? Cancer Chemother Pharmacol 67:1189–1190 (author reply 91–92)CrossRefPubMedGoogle Scholar
  24. 24.
    Hosseini R, Benton DC, Dunn PM et al (2001) SK3 is an important component of K(+) channels mediating the afterhyperpolarization in cultured rat SCG neurones. J Physiol 535:323–334CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Potier M, Joulin V, Roger S et al (2006) Identification of SK3 channel as a new mediator of breast cancer cell migration. Mol Cancer Ther 5:2946–2953CrossRefPubMedGoogle Scholar
  26. 26.
    Caussanel JP, Levi F, Brienza S et al (1990) Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate. J Natl Cancer Inst 82:1046–1050CrossRefPubMedGoogle Scholar
  27. 27.
    Lecomte T, Landi B, Beaune P et al (2006) Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res 12:3050–3056CrossRefPubMedGoogle Scholar
  28. 28.
    Gueguinou M, Harnois T, Crottes D et al (2016) SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline. Oncotarget 7:36168–36184CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Esfahani A, Somi MH, Ayromlou H et al (2016) The effect of n-3 polyunsaturated fatty acids on incidence and severity of oxaliplatin induced peripheral neuropathy: a randomized controlled trial. Biomark Res 4:13CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gamelin L, Capitain O, Morel A et al (2007) Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway. Clin Cancer Res 13:6359–6368CrossRefPubMedGoogle Scholar
  31. 31.
    Lopatin AN, Nichols CG (2001) Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol 33:625–638CrossRefPubMedGoogle Scholar
  32. 32.
    Nikolaev MV, Magazanik LG, Tikhonov DB (2012) Influence of external magnesium ions on the NMDA receptor channel block by different types of organic cations. Neuropharmacology 62:2078–2085CrossRefPubMedGoogle Scholar
  33. 33.
    Ferrier J, Bayet-Robert M, Pereira B et al (2013) A polyamine-deficient diet prevents oxaliplatin-induced acute cold and mechanical hypersensitivity in rats. PLoS One 8:e77828CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ngo-Anh TJ, Bloodgood BL, Lin M et al (2005) SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat Neurosci 8:642–649CrossRefPubMedGoogle Scholar
  35. 35.
    Austin CPH, Ma DJL, Mixson LA, Caskey CT (1999) Mapping of hKCa3 to chromosome 1q21 and investigation of linkage of CAG repeat polymorphism to schizophrenia. Mol Psychiatry 4:261CrossRefPubMedGoogle Scholar
  36. 36.
    Curtain R, Sundholm J, Lea R et al (2005) Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility. BMC Med Genet 6:32CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ivković MR, Tarasjev V, Orolicki A, Damjanović S, Paunović A (2006) Schizophrenia and Polymorphic Cag Repeats Array of Calcium-Activated Potassium Channel (Kcnn3) Gene in Serbian Population. Int J Neurosci 116:157–164CrossRefPubMedGoogle Scholar
  38. 38.
    Ujike H, Yamamoto A, Tanaka Y et al (2001) Association study of CAG repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder. Psychiatry Res 101:203–207CrossRefPubMedGoogle Scholar
  39. 39.
    Sander T, Scholz L, Janz D et al (1999) Length variation of a polyglutamine array in the gene encoding a small-conductance, calcium-activated potassium channel (hKCa3) and susceptibility to idiopathic generalized epilepsy. Epilepsy Res 33:227–233CrossRefPubMedGoogle Scholar
  40. 40.
    Koronyo-Hamaoui M, Gak E, Stein D et al (2004) CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population. Am J Med Genet Part B, Neuropsychiatric Genet 131B:76–80CrossRefGoogle Scholar
  41. 41.
    Saleem Q, Sreevidya VS, Sudhir J et al (2000) Association analysis of CAG repeats at the KCNN3 locus in Indian patients with bipolar disorder and schizophrenia. Am J Med Genet 96:744–748CrossRefPubMedGoogle Scholar
  42. 42.
    Tuteja D, Rafizadeh S, Timofeyev V et al (2010) Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels. Circ Res 107:851–859CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Benjamin Anon
    • 1
  • Bérenger Largeau
    • 2
  • Alban Girault
    • 3
  • Aurélie Chantome
    • 4
  • Morgane Caulet
    • 1
  • Clémence Perray
    • 1
  • Driffa Moussata
    • 1
  • Christophe Vandier
    • 4
  • Chantal Barin-Le Guellec
    • 2
    • 5
  • Thierry Lecomte
    • 1
    • 3
  1. 1.Department of Gastroenterology and Digestive Oncology, Service d’Hépato-gastro-entérologieHôpital Trousseau, CHRU de ToursToursFrance
  2. 2.Department of Molecular BiologyHôpital Bretonneau, CHRU de ToursToursFrance
  3. 3.UMR CNRS 7292 (GICC), Université François RabelaisToursFrance
  4. 4.INSERM, UMR 1069, Université François RabelaisToursFrance
  5. 5.INSERM, UMR 850, Université de LimogesLimogesFrance

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