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Bicarbonate transport inhibitor SITS modulates pH homeostasis triggering apoptosis of Dalton’s lymphoma: implication of novel molecular mechanisms

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Abstract

Bicarbonate transporter (BCT) plays a crucial role in maintaining pH homeostasis of tumor cells by import of \({\text{HCO}}_{3}^{ - } .\) This helps the tumor cells in manifesting extracellular tumor acidosis, accompanied by a relative intracellular alkalinization, which in turn promotes tumor progression. Therefore, blocking BCT-mediated \({\text{HCO}}_{3}^{ - }\) transport is envisaged as a promising anticancer therapeutic approach. Thus, using a murine model of a T cell lymphoma, designated as Dalton’s lymphoma (DL), in the present in vitro investigation the antitumor consequences of blocking BCT function by its inhibitor 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate (SITS) were explored. Treatment of DL cells with SITS resulted in an increase in the extracellular pH, associated with a decline in DL cell survival and augmented induction of apoptosis. BCT inhibition also elevated the expression of cytochrome c, caspase-9, caspase-3, Bax, reactive oxygen species, and nitric oxide along with inhibition of HSP-70 and Bcl2, which regulate tumor cell survival and apoptosis. SITS-treated DL cells displayed upregulated production of IFN-γ and IL-6 along with a decline of IL-10. Treatment of DL cells with SITS also inhibited the expression of fatty acid synthase, which is crucial for membrane biogenesis in neoplastic cells. The expression of lactate transporter MCT-1 and multidrug resistance regulating protein MRP-1 got inhibited along with hampered uptake of glucose and lactate production in SITS-treated DL cells. Thus, the declined tumor cell survival following inhibition of BCT could be the consequence of interplay of several inter-connected regulatory molecular events. The outcome of this study indicates the potential of BCT inhibition as a novel therapeutic approach for treatment of hematological malignancies.

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Abbreviations

DCFDA:

Dichlorodihydrofluorescein diacetate

DL:

Dalton’s lymphoma

EBSS:

Earle’s balanced salt solution

FASN:

Fatty acid synthase

HBSS:

Hank’s balanced salt solution

iNOS:

Inducible nitric oxide synthase

MRP-1:

Multidrug resistant associated protein-1

NO:

Nitric oxide

PIPES:

Piperazine-N,N′-bis(2-ethanesulfonic acid)

ROS:

Reactive oxygen species

SITS:

‘4-acetamido-4-isothiocyanostilbene-2,2-disulfonate’

SOCS:

Suppressor of cytokine signaling

References

  1. Vaupel P (2010) Metabolic microenvironment of tumor cells: a key factor in malignant progression. Exp Oncol 32:125–127

    PubMed  CAS  Google Scholar 

  2. Fang JS, Gillies RD, Gatenby RA (2008) Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol 18:330–337

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Paradise RK, Lauffenburger DA, Van Vliet KJ (2011) Acidic extracellular pH promotes activation of integrin alpha(v)beta(3). PLoS ONE 6:e15746

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10:767–777

    Article  PubMed  CAS  Google Scholar 

  5. Xu K, Mao XZ, Mehta M, Cui J, Zhang C, Mao FL, Xu Y (2013) Elucidation of how cancer cells avoid acidosis through comparative transcriptomic data analysis. PLoS ONE 8:e71177

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, Baba Y (2013) Acidic extracellular microenvironment and cancer. Cancer Cell Int 13:89

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549

    Article  PubMed  CAS  Google Scholar 

  8. Boedtkjer E, Bunch L, Pedersen SF (2012) Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy. Curr Pharm Des 18:1345–1371

    Article  PubMed  CAS  Google Scholar 

  9. Kumar A, Kant S, Singh SM (2013) Alpha-cyano-4-hydroxycinnamate induces apoptosis in Dalton’s lymphoma cells: role of altered cell survival-regulatory mechanisms. Anticancer Drugs 24:158–171

    Article  PubMed  CAS  Google Scholar 

  10. Vishvakarma NK, Singh SM (2011) Mechanisms of tumor growth retardation by modulation of pH regulation in the tumor-microenvironment of a murine T cell lymphoma. Biomed Pharmacother 65:27–39

    Article  PubMed  CAS  Google Scholar 

  11. Zhao Z, Wu MS, Zou C, Tang Q, Lu J, Liu D, Wu Y, Yin J, Xie X, Shen J, Kang T, Wang J (2014) Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-kappaB pathway. Cancer Lett 342:150–158

    Article  PubMed  CAS  Google Scholar 

  12. Calorini L, Peppicelli S, Bianchini F (2012) Extracellular acidity as favouring factor of tumor progression and metastatic dissemination. Exp Oncol 34:79–84

    PubMed  CAS  Google Scholar 

  13. Fukumura D, Jain RK (2007) Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 101:937–949

    Article  PubMed  CAS  Google Scholar 

  14. Gerweck LE, Vijayappa S, Kozin S (2006) Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther 5:1275–1279

    Article  PubMed  CAS  Google Scholar 

  15. Chen W, Zhong R, Ming J, Zou L, Zhu BB, Lu XZ, Ke JT, Zhang Y, Liu L, Miao X, Huang T (2012) The SLC4A7 variant rs4973768 is associated with breast cancer risk: evidence from a case–control study and a meta-analysis. Breast Cancer Res Treat 136:847–857

    Article  PubMed  CAS  Google Scholar 

  16. Boedtkjer E, Moreira JM, Mele M, Vahl P, Wielenga VT, Christiansen PM, Jensen VE, Pedersen SF, Aalkjaer C (2013) Contribution of Na+, HCO (−)3 -cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int J Cancer 132:1288–1299

    Article  PubMed  CAS  Google Scholar 

  17. Cordat E, Casey JR (2009) Bicarbonate transport in cell physiology and disease. Biochem J 417:423–439

    Article  PubMed  CAS  Google Scholar 

  18. Sarosi GA Jr, Jaiswal K, Herndon E, Lopez-Guzman C, Spechler SJ, Souza RF (2005) Acid increases MAPK-mediated proliferation in Barrett’s esophageal adenocarcinoma cells via intracellular acidification through a Cl−/HCO3 − exchanger. Am J Physiol Gastrointest Liver Physiol 289:G991–G997

    Article  PubMed  CAS  Google Scholar 

  19. Alper SL, Sharma AK (2013) The SLC26 gene family of anion transporters and channels. Mol Asp Med 34:494–515

    Article  CAS  Google Scholar 

  20. Parker MD, Boron WF (2013) The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 93:803–959

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Romero MF, Chen AP, Parker MD, Boron WF (2013) The SLC4 family of bicarbonate (HCO (−)(3) ) transporters. Mol Asp Med 34:159–182

    Article  CAS  Google Scholar 

  22. Mayer A, Vaupel P (2013) Hypoxia, lactate accumulation, and acidosis: siblings or accomplices driving tumor progression and resistance to therapy? Adv Exp Med Biol 789:203–209

    Article  PubMed  CAS  Google Scholar 

  23. McDonald PC, Winum JY, Supuran CT, Dedhar S (2012) Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 3:84–97

    PubMed  PubMed Central  Google Scholar 

  24. Wong P, Kleemann HW, Tannock IF (2002) Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. Br J Cancer 87:238–245

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Liu CJ, Hwang JM, Wu TT, Hsieh YH, Wu CC, Hsieh YS, Tsai CH, Wu HC, Huang CY, Liu JY (2008) Anion exchanger inhibitor DIDS induces human poorly-differentiated malignant hepatocellular carcinoma HA22T cell apoptosis. Mol Cell Biochem 308:117–125

    Article  PubMed  CAS  Google Scholar 

  26. Wu TT, Hsieh YH, Wu CC, Tsai JH, Hsieh YS, Huang CY, Liu JY (2006) Overexpression of anion exchanger 2 in human hepatocellular carcinoma. Chin J Physiol 49:192–198

    PubMed  CAS  Google Scholar 

  27. De Giusti VC, Orlowski A, Villa-Abrille MC, de Cingolani GEC, Casey JR, Alvarez BV, Aiello EA (2011) Antibodies against the cardiac sodium/bicarbonate co-transporter (NBCe1) as pharmacological tools. Br J Pharmacol 164:1976–1989

    Article  PubMed  PubMed Central  Google Scholar 

  28. Boron WF, Chen L, Parker MD (2009) Modular structure of sodium-coupled bicarbonate transporters. J Exp Biol 212:1697–1706

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Zhou J, Mauerer K, Farina L, Gribben JG (2005) The role of the tumor microenvironment in hematological malignancies and implication for therapy. Front Biosci 10:1581–1596

    Article  PubMed  CAS  Google Scholar 

  30. Kant S, Kumar A, Singh SM (2014) Tumor growth retardation and chemosensitizing action of fatty acid synthase inhibitor orlistat on T cell lymphoma: implication of reconstituted tumor microenvironment and multidrug resistance phenotype. Biochim Biophys Acta 1840:294–302

    Article  PubMed  CAS  Google Scholar 

  31. Shanker A, Singh SM, Sodhi A (2000) Ascitic growth of a spontaneous transplantable T cell lymphoma induces thymic involution—1. Alterations in the CD4/CD8 distribution in thymocytes. Tumor Biol 21:288–298

    Article  CAS  Google Scholar 

  32. Kumar A, Vishvakarma NK, Tyagi A, Bharti AC, Singh SM (2012) Anti-neoplastic action of aspirin against a T-cell lymphoma involves an alteration in the tumour microenvironment and regulation of tumour cell survival. Biosci Rep 32:91–104

    Article  PubMed  CAS  Google Scholar 

  33. Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68:1003–1011

    Article  PubMed  CAS  Google Scholar 

  34. Franck P, Petitipain N, Cherlet M, Dardennes M, Maachi F, Schutz B, Poisson L, Nabet P (1996) Measurement of intracellular pH in cultured cells by flow cytometry with BCECF-AM. J Biotechnol 46:187–195

    Article  PubMed  CAS  Google Scholar 

  35. Gewies A, Rokhlin OW, Cohen MB (2000) Cytochrome c is involved in Fas-mediated apoptosis of prostatic carcinoma cell lines. Cancer Res 60:2163–2168

    PubMed  CAS  Google Scholar 

  36. Brender C, Columbus R, Metcalf D, Handman E, Starr R, Huntington N, Tarlinton D, Odum N, Nicholson SE, Nicola NA, Hilton DJ, Alexander WS (2004) SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol Cell Biol 24:6094–6103

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Seki Y, Hayashi K, Matsumoto A, Seki N, Tsukada J, Ransom J, Naka T, Kishimoto T, Yoshimura A, Kubo M (2002) Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc Natl Acad Sci USA 99:13003–13008

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Chung HT, Pae HO, Choi BM, Billiar TR, Kim YM (2001) Nitric oxide as a bioregulator of apoptosis. Biochem Biophys Res Commun 282:1075–1079

    Article  PubMed  CAS  Google Scholar 

  39. Huerta-Yepez S, Vega M, Escoto-Chavez SE, Murdock B, Sakai T, Baritaki S, Bonavida B (2009) Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1. Nitric Oxide 20:39–52

    Article  PubMed  CAS  Google Scholar 

  40. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418

    Article  PubMed  CAS  Google Scholar 

  41. Menendez JA, Decker JP, Lupu R (2005) In support of Fatty Acid Synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells. J Cell Biochem 94:1–4

    Article  PubMed  CAS  Google Scholar 

  42. Thews O, Gassner B, Kelleher DK, Schwerdt G, Gekle M (2006) Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8:143–152

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Zhou SF (2008) Role of multidrug resistance associated proteins in drug development. Drug Discov Ther 2:305–332

    PubMed  CAS  Google Scholar 

  44. Wijnholds J (2002) Drug resistance caused by multidrug resistance-associated proteins. Novartis Found Symp 243:69–79

    Article  PubMed  CAS  Google Scholar 

  45. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181

    Article  PubMed  CAS  Google Scholar 

  46. Hulikova A, Vaughan-Jones RD, Swietach P (2011) Dual role of CO2/HCO (−)3 buffer in the regulation of intracellular pH of three-dimensional tumor growths. J Biol Chem 286:13815–13826

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Park HJ, Makepeace CM, Lyons JC, Song CW (1996) Effect of intracellular acidity and ionomycin on apoptosis in HL-60 cells. Eur J Cancer 32A:540–546

    Article  PubMed  CAS  Google Scholar 

  48. Pan XY, Chen GQ, Cai L, Buscemi S, Fu GH (2006) Anion exchanger 2 mediates the action of arsenic trioxide. Br J Haematol 134:491–499

    Article  PubMed  CAS  Google Scholar 

  49. Heimlich G, Cidlowski JA (2006) Selective role of intracellular chloride in the regulation of the intrinsic but not extrinsic pathway of apoptosis in Jurkat T-cells. J Biol Chem 281:2232–2241

    Article  PubMed  CAS  Google Scholar 

  50. Willis S, Day CL, Hinds MG, Huang DCS (2003) The Bcl-2-regulated apoptotic pathway. J Cell Sci 116:4053–4056

    Article  PubMed  CAS  Google Scholar 

  51. Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124

    Article  PubMed  CAS  Google Scholar 

  52. Peng X, Gandhi V (2012) ROS-activated anticancer prodrugs: a new strategy for tumor-specific damage. Ther Deliv 3:823–833

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Xu WM, Liu LZ, Loizidou M, Ahmed M, Charles IG (2002) The role of nitric oxide in cancer. Cell Res 12:311–320

    Article  PubMed  Google Scholar 

  54. Yang J, Wu LJ, Tashino SI, Onodera S, Ikejima T (2008) Reactive oxygen species and nitric oxide regulate mitochondria-dependent apoptosis and autophagy in evodiamine-treated human cervix carcinoma HeLa cells. Free Radic Res 42:492–504

    Article  PubMed  CAS  Google Scholar 

  55. Riemann A, Schneider B, Ihling A, Nowak M, Sauvant C, Thews O, Gekle M (2011) Acidic environment leads to ROS-induced MAPK signaling in cancer cells. PLoS ONE 6:e22445

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22

    Article  PubMed  CAS  Google Scholar 

  57. Ahn EY, Pan G, Vickers SM, McDonald JM (2002) IFN-gamma upregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma. Int J Cancer 100:445–451

    Article  PubMed  CAS  Google Scholar 

  58. Alas S, Emmanouilides C, Bonavida B (2001) Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin’s lymphoma to apoptosis. Clin Cancer Res 7:709–723

    PubMed  CAS  Google Scholar 

  59. Howell WM, Rose-Zerilli MJ (2006) Interleukin-10 polymorphisms, cancer susceptibility and prognosis. Fam Cancer 5:143–149

    Article  PubMed  CAS  Google Scholar 

  60. Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13:95–109

    Article  PubMed  CAS  Google Scholar 

  61. Itakura E, Huang RR, Wen DR, Paul E, Wunsch PH, Cochran AJ (2011) IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. Mod Pathol 24:801–809

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Kitasato A, Tajima Y, Kuroki T, Tsutsumi R, Adachi T, Mishima T, Kanematsu T (2007) Inflammatory cytokines promote inducible nitric oxide synthase-mediated DNA damage in hamster gallbladder epithelial cells. World J Gastroenterol 13:6379–6384

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Klausen P, Pedersen L, Jurlander J, Baumann H (2000) Oncostatin M and interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG2 cells. Oncogene 19:3675–3683

    Article  PubMed  CAS  Google Scholar 

  64. Wall L, Burke F, Barton C, Smyth J, Balkwill F (2003) IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro. Clin Cancer Res 9:2487–2496

    PubMed  CAS  Google Scholar 

  65. Yang D, Elner SG, Bian ZM, Till GO, Petty HR, Elner VM (2007) Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 85:462–472

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Balligand JL, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein CJ, Davidoff AJ, Kelly RA et al (1994) Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem 269:27580–27588

    PubMed  CAS  Google Scholar 

  67. Guo Z, Shao L, Du Q, Park KS, Geller DA (2007) Identification of a classic cytokine-induced enhancer upstream in the human iNOS promoter. FASEB J 21:535–542

    Article  PubMed  CAS  Google Scholar 

  68. Moran DM, Mayes N, Koniaris LG, Cahill PA, McKillop IH (2005) Interleukin-6 inhibits cell proliferation in a rat model of hepatocellular carcinoma. Liver Int 25:445–457

    Article  PubMed  CAS  Google Scholar 

  69. Cavarretta IT, Neuwirt H, Untergasser G, Moser PL, Zaki MH, Steiner H, Rumpold H, Fuchs D, Hobisch A, Nemeth JA, Culig Z (2007) The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1. Oncogene 26:2822–2832

    Article  PubMed  CAS  Google Scholar 

  70. Menendez JA (2010) Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives. Biochim Biophys Acta 1801:381–391

    Article  PubMed  CAS  Google Scholar 

  71. Liu H, Liu JY, Wu X, Zhang JT (2010) Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int J Biochem Mol Biol 1:69–89

    PubMed  CAS  PubMed Central  Google Scholar 

  72. Le Vee M, Jouan E, Moreau A, Fardel O (2011) Regulation of drug transporter mRNA expression by interferon-gamma in primary human hepatocytes. Fundam Clin Pharmacol 25:99–103

    Article  PubMed  Google Scholar 

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Acknowledgments

The financial support to the School of Biotechnology from DBT, UGC University with potential for excellence program and the DST-PURSE Program, Government of India, New Delhi is acknowledged. The authors express gratitude to DBT and CSIR New Delhi, for fellowship support to Shiva Kant (DBT-JRF/2010-11/79) and Ajay Kumar (09/013(0329)/2010-EMR-I), respectively. The help of Dr. S. D. Singh of Parul Pathology Laboratory is gratefully acknowledged for some biochemical assays. The author expresses gratitude to Dr. Syamal Roy (IICB Kolkata) for providing antibody of MRP.

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  1. School of Biotechnology, Banaras Hindu University, Varanasi, 221005, India

    Shiva Kant, Ajay Kumar & Sukh Mahendra Singh

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  1. Shiva Kant
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Correspondence to Sukh Mahendra Singh.

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Kant, S., Kumar, A. & Singh, S.M. Bicarbonate transport inhibitor SITS modulates pH homeostasis triggering apoptosis of Dalton’s lymphoma: implication of novel molecular mechanisms. Mol Cell Biochem 397, 167–178 (2014). https://doi.org/10.1007/s11010-014-2184-2

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