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Hypoxia-induced mobilization of NHE6 to the plasma membrane triggers endosome hyperacidification and chemoresistance

Lucien, Fabrice, Pelletier, Pierre-Paul, Lavoie, Roxane R., Lacroix, Jean-Michel, Roy, Sébastien, Parent, Jean-Luc, Arsenault, Dominique, Harper, Kelly, Dubois, Claire M.·2017·Nature Communications
DOI 10.1038/ncomms15884PMC PMC5482059
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Abstract

The pH-dependent partitioning of chemotherapeutic drugs is a fundamental yet understudied drug distribution mechanism that may underlie the low success rates of current approaches to counter multidrug resistance (MDR). This mechanism is influenced by the hypoxic tumour microenvironment and results in selective trapping of weakly basic drugs into acidified compartments such as the extracellular environment. Here we report that hypoxia not only leads to acidification of the tumour microenvironment but also induces endosome hyperacidification. The acidity of the vesicular lumen, together with the alkaline pH of the cytoplasm, gives rise to a strong intracellular pH gradient that drives intravesicular drug trapping and chemoresistance. Endosome hyperacidification is due to the relocalization of the Na+/H+ exchanger isoform 6 (NHE6) from endosomes to the plasma membrane, an event that involves binding of NHE6 to the activated protein kinase C–receptor for activated C kinase 1 complex. These findings reveal a novel mechanism of hypoxia-induced MDR that involves the aberrant intracellular distribution of NHE6.

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Research works printed but not linked: 62

  1. Vermorken, J. B. The role of anthracyclines in second-line therapy of ovarian cancer. Int. J. Gynecol. Cancer 13, (Suppl 2): 178–184 (2003). · DOI
  2. Oostendorp, L. J., Stalmeier, P. F., Donders, A. R., van der Graaf, W. T. & Ottevanger, P. B. Efficacy and safety of palliative chemotherapy for patients with advanced breast cancer pretreated with anthracyclines and taxanes: a systematic review. Lancet Oncol. 12, 1053–1061 (2011). · DOI
  3. Childhood Acute Lymphoblastic Leukaemia Collaborative, G. Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis. Br. J. Haematol. 145, 376–388 (2009). · DOI
  4. Valero, V. et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J. Clin. Oncol. 13, 2886–2894 (1995). · DOI
  5. Kim, S. B. et al. Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline: randomized phase II multicenter trial. Invest. New Drugs 32, 753–761 (2014). · DOI
  6. Wojtkowiak, J. W., Verduzco, D., Schramm, K. J. & Gillies, R. J. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol. Pharmacol. 8, 2032–2038 (2011). · DOI
  7. Baguley, B. C. Multiple drug resistance mechanisms in cancer. Mol. Biotechnol. 46, 308–316 (2010). · DOI
  8. Lotz, C. et al. Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells. Oncol. Rep. 17, 239–244 (2007).
  9. Thews, O., Gassner, B., Kelleher, D. K., Schwerdt, G. & Gekle, M. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8, 143–152 (2006). · DOI
  10. Alfarouk, K. O. et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int. 15, 71 (2015). · DOI
  11. Zhitomirsky, B. & Assaraf, Y. G. Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. Oncotarget 6, 1143–1156 (2015). · DOI
  12. Avnet, S. et al. Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance. Oncotarget 7, 63408–63423 (2016). · DOI
  13. Raghunand, N., Mahoney, B. P. & Gillies, R. J. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem. Pharmacol. 66, 1219–1229 (2003). · DOI
  14. Mahoney, B. P., Raghunand, N., Baggett, B. & Gillies, R. J. Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem. Pharmacol. 66, 1207–1218 (2003). · DOI
  15. Zhitomirsky, B. & Assaraf, Y. G. Lysosomes as mediators of drug resistance in cancer. Drug Resist. Update 24, 23–33 (2016). · DOI
  16. Fuster, D. G. & Alexander, R. T. Traditional and emerging roles for the SLC9 Na+/H+ exchangers. Pflugers Arch. 466, 61–76 (2014). · DOI · Paper page
  17. Casey, J. R., Grinstein, S. & Orlowski, J. Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol. 11, 50–61 (2010). · DOI · Paper page
  18. Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008). · DOI · Paper page
  19. Kondapalli, K. C., Prasad, H. & Rao, R. An inside job: how endosomal Na(+)/H(+) exchangers link to autism and neurological disease. Front. Cell Neurosci. 8, 172 (2014). · DOI
  20. Kondapalli, K. C. et al. A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma. Nat. Commun. 6, 6289 (2015). · DOI
  21. Chen, J. et al. NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/beta-catenin pathway and Bcl-2 expression. Oncotarget. 6, 12405–12420 (2015). · DOI
  22. Lucien, F., Brochu-Gaudreau, K., Arsenault, D., Harper, K. & Dubois, C. M. Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PLoS ONE 6, e28851 (2011). · DOI
  23. Gerweck, L. E., Kozin, S. V. & Stocks, S. J. The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells. Br. J. Cancer 79, 838–842 (1999). · DOI
  24. Altan, N., Chen, Y., Schindler, M. & Simon, S. M. Defective acidification in human breast tumor cells and implications for chemotherapy. J. Exp. Med. 187, 1583–1598 (1998). · DOI
  25. Lucien, F., Harper, K., Pelletier, P. P., Volkov, L. & Dubois, C. M. Simultaneous pH measurement in endocytic and cytosolic compartments in living cells using confocal microscopy. J. Vis. Exp. 28, 1–7 (2014).
  26. Ohgaki, R., Fukura, N., Matsushita, M., Mitsui, K. & Kanazawa, H. Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with RACK1. J. Biol. Chem. 283, 4417–4429 (2008). · DOI
  27. Xinhan, L. et al. Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. Am. J. Physiol. Cell. Physiol. 301, C1431–C1444 (2011). · DOI
  28. Ruan, Y. et al. Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma. J. Clin. Invest. 122, 2554–2566 (2012). · DOI
  29. Ron, D. et al. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc. Natl Acad. Sci. USA 91, 839–843 (1994). · DOI
  30. Rigas, A. C., Ozanne, D. M., Neal, D. E. & Robson, C. N. The scaffolding protein RACK1 interacts with androgen receptor and promotes cross-talk through a protein kinase C signaling pathway. J. Biol. Chem. 278, 46087–46093 (2003). · DOI
  31. Liedtke, C. M., Yun, C. H., Kyle, N. & Wang, D. Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor. J. Biol. Chem. 277, 22925–22933 (2002). · DOI
  32. Bird, R. J., Baillie, G. S. & Yarwood, S. J. Interaction with receptor for activated C-kinase 1 (RACK1) sensitizes the phosphodiesterase PDE4D5 towards hydrolysis of cAMP and activation by protein kinase C. Biochem. J. 432, 207–216 (2010). · DOI
  33. Park, H. Y., Wu, H., Killoran, C. E. & Gilchrest, B. A. The receptor for activated C-kinase-I (RACK-I) anchors activated PKC-beta on melanosomes. J. Cell Sci. 117, 3659–3668 (2004). · DOI
  34. Parent, A., Laroche, G., Hamelin, E. & Parent, J. L. RACK1 regulates the cell surface expression of the G protein-coupled receptor for thromboxane A(2). Traffic 9, 394–407 (2008). · DOI
  35. Ribatti, D. The chick embryo chorioallantoic membrane in the study of tumor angiogenesis. Rom. J. Morphol. Embryol. 49, 131–135 (2008).
  36. Rademakers, S. E., Lok, J., van der Kogel, A. J., Bussink, J. & Kaanders, J. H. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer 11, 167 (2011). · DOI
  37. Shin, K. H. et al. Detecting changes in tumor hypoxia with carbonic anhydrase IX and pimonidazole. Cancer Biol. Ther. 6, 70–75 (2007). · DOI
  38. Li, X. F. et al. Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res. 67, 7646–7653 (2007). · DOI
  39. De Milito, A. & Fais, S. Tumor acidity, chemoresistance and proton pump inhibitors. Fut. Oncol. 1, 779–786 (2005). · DOI
  40. Taylor, S. et al. Microenvironment acidity as a major determinant of tumor chemoresistance: proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist. Update 23, 69–78 (2015). · DOI
  41. Harguindey, S., Arranz, J. L., Wahl, M. L., Orive, G. & Reshkin, S. J. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 29, 2127–2136 (2009).
  42. Parks, S. K., Chiche, J. & Pouyssegur, J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat. Rev. Cancer 13, 611–623 (2013). · DOI
  43. Hashim, A. I., Zhang, X., Wojtkowiak, J. W., Martinez, G. V. & Gillies, R. J. Imaging pH and metastasis. NMR Biomed. 24, (2011). · DOI
  44. Gillies, R. J., Raghunand, N., Karczmar, G. S. & Bhujwalla, Z. M. MRI of the tumor microenvironment. J. Magn. Reson. Imaging 16, 430–450 (2002). · DOI
  45. Madshus, I. H. Regulation of intracellular pH in eukaryotic cells. Biochem. J. 250, 1–8 (1988). · DOI
  46. Gerweck, L. E. & Seetharaman, K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 56, 1194–1198 (1996).
  47. Gerweck, L. E., Vijayappa, S. & Kozin, S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol. Cancer Ther. 5, 1275–1279 (2006). · DOI · Paper page
  48. Raghunand, N. et al. Enhancement of chemotherapy by manipulation of tumour pH. Br. J. Cancer 80, 1005–1011 (1999). · DOI
  49. Harguindey, S. et al. Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs-an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. J. Transl. Med. 11, 282 (2013). · DOI
  50. Sharma, M. et al. pH gradient reversal: an emerging hallmark of cancers. Recent Pat. Anticancer Drug Discov. 10, 244–258 (2015). · DOI
  51. Miraglia, E. et al. Na+/H+ exchanger activity is increased in doxorubicin-resistant human colon cancer cells and its modulation modifies the sensitivity of the cells to doxorubicin. Int. J. Cancer 115, 924–929 (2005). · DOI
  52. Jin, W. et al. Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na+/H+ exchanger. Cancer Lett. 308, 81–90 (2011). · DOI
  53. Pusztai, L. et al. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 104, 682–691 (2005). · DOI
  54. Li, D., Zhou, L., Huang, J. & Xiao, X. Effect of multidrug resistance 1/P-glycoprotein on the hypoxia-induced multidrug resistance of human laryngeal cancer cells. Oncol. Lett. 12, 1569–1574 (2016). · DOI
  55. Chen, A. et al. Photoacoustic ‘nanobombs’ fight against undesirable vesicular compartmentalization of anticancer drugs. Sci. Rep. 5, 15527 (2015). · DOI
  56. Brett, C. L., Wei, Y., Donowitz, M. & Rao, R. Human Na(+)/H(+) exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am. J. Physiol. Cell Physiol. 282, C1031–C1041 (2002). · DOI · Paper page
  57. Prior, M. J. et al. Quantitative proteomic analysis of the adipocyte plasma membrane. J. Proteome Res. 10, 4970–4982 (2011). · DOI
  58. Liu, L., Schlesinger, P. H., Slack, N. M., Friedman, P. A. & Blair, H. C. High capacity Na+/H+ exchange activity in mineralizing osteoblasts. J. Cell Physiol. 226, 1702–1712 (2011). · DOI
  59. Pulakat, L. et al. Ligand-dependent complex formation between the angiotensin II receptor subtype AT2 and Na+/H+ exchanger NHE6 in mammalian cells. Peptides 26, 863–873 (2005). · DOI
  60. Paolicchi, E. et al. Targeting hypoxic response for cancer therapy. Oncotarget 7, 13464–13478 (2016). · DOI
  61. Charbonneau, M. et al. Hypoxia-inducible factor mediates hypoxic and tumor necrosis factor alpha-induced increases in tumor necrosis factor-alpha converting enzyme/ADAM17 expression by synovial cells. J. Biol. Chem. 282, 33714–33724 (2007). · DOI
  62. Leong, H. S. et al. Intravital imaging of embryonic and tumor neovasculature using viral nanoparticles. Nat. Protoc. 5, 1406–1417 (2010). · DOI

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Metadata

Authors
Lucien, F., Pelletier, P.-P., Lavoie, R. R., Lacroix, J.-M., Roy, S., Parent, J.-L., Arsenault, D., Harper, K., & Dubois, C. M.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-06-21
Volume
8
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms15884
PMC
PMC5482059
Cited by
66
References
5
Language
en
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