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Apoptosis

, Volume 18, Issue 12, pp 1574–1585 | Cite as

Targeting monocarboxylate transporter by α-cyano-4-hydroxycinnamate modulates apoptosis and cisplatin resistance of Colo205 cells: implication of altered cell survival regulation

  • Ajay Kumar
  • Shiva Kant
  • Sukh Mahendra SinghEmail author
Original Paper

Abstract

The present investigation was undertaken to study the effect of in vitro exposure of Colo205, colonadenocarcinoma cells, to monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamate (αCHC) on cell survival and evolution of resistance to chemotherapeutic drug cisplatin. αCHC-treated Colo205 cells showed inhibition of survival accompanied by an augmented induction of apoptosis. Changes in cell survival properties were associated with alterations in lactate efflux, pH homeostasis, expression of glucose transporters, glucose uptake, HIF-1α, generation of nitric oxide, expression pattern of some key cell survival regulatory molecules: Bcl2, Bax, active caspase-3 and p53. Pretreatment of Colo205 cells with αCHC also altered their susceptibility to the cytotoxicity of cisplatin accompanied by altered expression of multidrug resistance regulating MDR1 and MRP1 genes. This study for the first time deciphers some of the key molecular events underlying modulation of cell survival of cancer cells of colorectal origin by αCHC and its contribution to chemosensitization against cisplatin. Thus these findings will be of immense help in further research for optimizing the use of αCHC for improving the chemotherapeutic efficacy of anticancer drugs like cisplatin.

Keywords

Apoptosis Cisplatin α-Cyano-4-hydroxycinnamate (αCHC) Monocarboxylate transporter (MCT) Multidrug resistance 

Abbreviations

αCHC

α-Cyano-4-hydroxycinnamate

GLUT

Glucose transporter

HIF-1α

Hypoxia-inducible factor 1 alpha

pHi

Intracellular pH

MDR

Multidrug resistance

MCT

Monocarboxylate transporter

NO

Nitric oxide

RT-PCR

Reverse transcription-polymerase chain reaction

Notes

Acknowledgments

The financial support to the School of Biotechnology from DBT, New Delhi, and Grants from Interdisciplinary School of Lifesciences, Faculty of Science and UGC for Grant of University with Potential for Excellence is acknowledged. The authors express gratitude to CSIR and DBT, New Delhi, for fellowship support to Ajay Kumar (09/013(0329)/2010-EMR-I) and Shiva Kant (DBT-JRF/2010-11/79), respectively. The help of Dr. S.D. Singh of Parul Pathology laboratory is gratefully acknowledged for some biochemical assays.

Conflict of interest

None declared.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 6:69–90CrossRefGoogle Scholar
  2. 2.
    Galon J, Fridman WH, Pagès F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886PubMedCrossRefGoogle Scholar
  3. 3.
    Cammarota R, Bertolini V, Pennesi G et al (2010) The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker. J Transl Med 8:112PubMedCrossRefGoogle Scholar
  4. 4.
    Peddareddigari VG, Wang D, Dubois RN (2010) The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron 3:149–166PubMedCrossRefGoogle Scholar
  5. 5.
    Ogino S, Giovannucci E (2012) Commentary: lifestyle factors and colorectal cancer microsatellite instability–molecular pathological epidemiology science, based on unique tumour principle. Int J Epidemiol 41:1072–1074PubMedCrossRefGoogle Scholar
  6. 6.
    Yamakuchi M, Yagi S, Ito T, Lowenstein CJ (2011) MicroRNA-22 regulates hypoxia signaling in colon cancer cells. PLoS One 6:e20291PubMedCrossRefGoogle Scholar
  7. 7.
    Yeung TM, Gandhi SC, Bodmer WF (2011) Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci USA 108:4382–4387PubMedCrossRefGoogle Scholar
  8. 8.
    Xue X, Taylor M, Anderson E et al (2012) Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res 72:2285–2293PubMedCrossRefGoogle Scholar
  9. 9.
    Ehrmann-Jósko A, Siemińska J, Górnicka B, Ziarkiewicz-Wróblewska B, Ziółkowski B, Muszyński J (2006) Impaired glucose metabolism in colorectal cancer. Scand J Gastroenterol 41:1079–1086PubMedCrossRefGoogle Scholar
  10. 10.
    Ehrmann-Jósko A, Siemińska J, Górnicka B, Ziarkiewicz-Wróblewska B, Ziółkowski B, Muszyński J (2011) Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One 6:e24411CrossRefGoogle Scholar
  11. 11.
    Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637PubMedCrossRefGoogle Scholar
  12. 12.
    Le Floch R, Chiche J, Marchiq I et al (2011) CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci USA 108:16663–16668PubMedCrossRefGoogle Scholar
  13. 13.
    Baba M, Inoue M, Itoh K, Nishizawa Y (2008) Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. Biochem Biophys Res Commun 374:111–116PubMedCrossRefGoogle Scholar
  14. 14.
    Sonveaux P, Végran F, Schroeder T et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942PubMedGoogle Scholar
  15. 15.
    Espinoza AM, Venook AP (2011) Lactic acidosis and colon cancer: oncologic emergency? Clin Colorectal Cancer 10:194–197PubMedGoogle Scholar
  16. 16.
    Végran F, Boidot R, Michiels C, Sonveaux P, Feron O (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71:2550–2560PubMedCrossRefGoogle Scholar
  17. 17.
    Pinheiro C, Reis RM, Ricardo S, Longatto-Filho A, Schmitt F, Baltazar F (2010) Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol 2010:427694PubMedCrossRefGoogle Scholar
  18. 18.
    Halestrap AP, Meredith D (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628PubMedCrossRefGoogle Scholar
  19. 19.
    Halestrap AP (2012) The monocarboxylate transporter family–structure and functional characterization. IUBMB Life 64:1–9PubMedCrossRefGoogle Scholar
  20. 20.
    Kennedy KM, Dewhirst MW (2010) Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 6:127–148PubMedCrossRefGoogle Scholar
  21. 21.
    Pinheiro C, Longatto-Filho A, Azevedo-Silva J, Casal M, Schmitt FC, Baltazar F (2012) Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr 44:127–139PubMedCrossRefGoogle Scholar
  22. 22.
    Webb BA, Chimenti M, Jacobson MP, Barber DL (2011) Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11:671–677PubMedCrossRefGoogle Scholar
  23. 23.
    Izumi H, Torigoe T, Ishiguchi H et al (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549PubMedCrossRefGoogle Scholar
  24. 24.
    Mathupala SP, Colen CB, Parajuli P, Sloan AE (2007) Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis. J Bioenerg Biomembr 39:73–77PubMedCrossRefGoogle Scholar
  25. 25.
    Kumar A, Kant S, Singh SM (2013) α-Cyano-4-hydroxycinnamate induces apoptosis in Dalton’s lymphoma cells: role of altered cell survival-regulatory mechanisms. Anticancer Drugs 24:158–171PubMedCrossRefGoogle Scholar
  26. 26.
    Colen CB, Seraji-Bozorgzad N, Marples B, Galloway MP, Sloan AE, Mathupala SP (2006) Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study. Neurosurgery 59:1313–1323PubMedCrossRefGoogle Scholar
  27. 27.
    Colen CB, Shen Y, Ghoddoussi F et al (2011) Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia 13:620–632PubMedGoogle Scholar
  28. 28.
    Fang J, Quinones QJ, Holman TL et al (2006) The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol 70:2108–2115PubMedCrossRefGoogle Scholar
  29. 29.
    Simchowitz L, Davis AO (1991) Internal alkalinization by reversal of anion exchange in human neutrophils: regulation of transport by pH. Am J Physiol 260:132–142Google Scholar
  30. 30.
    Brivet M, Garcia-Cazorla A, Lyonnet S et al (2003) Impaired mitochondrial pyruvate importation in a patient and a fetus at risk. Mol Genet Metab 78:186–192PubMedCrossRefGoogle Scholar
  31. 31.
    Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234PubMedCrossRefGoogle Scholar
  32. 32.
    Pérez-Tomás R (2006) Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem 13:1859–1876PubMedCrossRefGoogle Scholar
  33. 33.
    Wahl ML, Owen JA, Burd R et al (2002) Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol Cancer Ther 1:617–628PubMedGoogle Scholar
  34. 34.
    Franck P, Petitipain N, Cherlet M et al (1996) Measurement of intracellular pH in cultured cells by flow cytometry with BCECF-AM. J Biotechnol 46:187–195PubMedCrossRefGoogle Scholar
  35. 35.
    Kumar A, Singh SM (2012) Priming effect of aspirin for tumor cells to augment cytotoxic action of cisplatin against tumor cells: implication of altered constitution of tumor microenvironment, expression of cell cycle, apoptosis, and survival regulatory molecules. Mol Cell Biochem 371:43–54PubMedCrossRefGoogle Scholar
  36. 36.
    Vishvakarma NK, Kumar A, Kumar A, Kant S, Bharti AC, Singh SM (2012) Myelopotentiating effect of curcumin in tumor-bearing host: role of bone marrow resident macrophages. Toxicol Appl Pharmacol 263:111–121PubMedCrossRefGoogle Scholar
  37. 37.
    Vishvakarma NK, Kumar A, Singh SM (2011) Role of curcumin-dependent modulation of tumor microenvironment of a murine T cell lymphoma in altered regulation of tumor cell survival. Toxicol Appl Pharmacol 252:298–306PubMedCrossRefGoogle Scholar
  38. 38.
    Kant S, Kumar A, Singh SM (2012) Fatty acid synthase inhibitor orlistat induces apoptosis in T cell lymphoma: role of cell survival regulatory molecules. Biochim Biophys Acta 1820:1764–1773PubMedCrossRefGoogle Scholar
  39. 39.
    Kumar A, Kant S, Singh SM (2012) Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: implication of altered glucose metabolism, pH homeostasis and cell survival regulation. Chem Biol Interact 199:29–37PubMedCrossRefGoogle Scholar
  40. 40.
    Ding AH, Nathan CF, Stuehr DJ (1988) Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages Comparison of activating cytokines and evidence for independent production. J Immunol 141:2407–2412PubMedGoogle Scholar
  41. 41.
    Somoza B, Guzman R, Cano V et al (2007) Induction of cardiac uncoupling protein-2 expression and adenosine 5′-monophosphate- activated protein kinase phosphorylation during early states of diet-induced obesity in mice. Endocrinology 148:924–931PubMedCrossRefGoogle Scholar
  42. 42.
    Chaudhuri RK, Mukherjee M, Sengupta D, Mazumder S (2006) Limitation of glucose oxidase method of glucose estimation in jaundiced neonates. Indian J Exp Biol 44:254–255PubMedGoogle Scholar
  43. 43.
    Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP (2012) Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem 113:2474–2487PubMedCrossRefGoogle Scholar
  44. 44.
    Kim MY, Trudel LJ, Wogan GN (2009) Apoptosis induced by capsaicin and resveratrol in colon carcinoma cells requires nitric oxide production and caspase activation. Anticancer Res 29:3733–3740PubMedGoogle Scholar
  45. 45.
    Gao J, Liu X, Rigas B (2005) Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress. Proc Natl Acad Sci USA 102:17207–17212PubMedCrossRefGoogle Scholar
  46. 46.
    Chau Q, Stewart DJ (1999) Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant. Cancer Chemother Pharmacol 44:193–202PubMedCrossRefGoogle Scholar
  47. 47.
    Epand RF, Epand RM, Gupta RS, Cragoe EJ Jr (1991) Reversal of intrinsic multidrug resistance in Chinese hamster ovary cells by amiloride analogs. Br J Cancer 63:247–251PubMedCrossRefGoogle Scholar
  48. 48.
    Simon S, Roy D, Schindler M (1994) Intracellular pH and the control of multidrug resistance. Proc Natl Acad Sci USA 91:1128–1132PubMedCrossRefGoogle Scholar
  49. 49.
    Wong P, Lee C, Tannock IF (2005) Reduction of intracellular pH as a strategy to enhance the pH-dependent cytotoxic effects of melphalan for human breast cancer cells. Clin Cancer Res 11:3553–3557PubMedCrossRefGoogle Scholar
  50. 50.
    Lu Y, Pang T, Wang J, Xiong D, Ma L et al (2008) Down-regulation of P-glycoprotein expression by sustained intracellular acidification in K562/Dox cells. Biochem Biophys Res Commun 377:441–446PubMedCrossRefGoogle Scholar
  51. 51.
    Zhu H, Chen XP, Luo SF et al (2005) Involvement of hypoxia-inducible factor-1-alpha in multidrug resistance induced by hypoxia in HepG2 cells. J Exp Clin Cancer Res 24:565–574PubMedGoogle Scholar
  52. 52.
    Milane L, Duan Z, Amiji M (2011) Role of hypoxia and glycolysis in the development of multi-drug resistance in human tumor cells and the establishment of an orthotopic multi-drug resistant tumor model in nude mice using hypoxic pre-conditioning. Cancer Cell Int 11:3PubMedCrossRefGoogle Scholar
  53. 53.
    Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L et al (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65:613–621PubMedCrossRefGoogle Scholar
  54. 54.
    Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281:9030–9037PubMedCrossRefGoogle Scholar
  55. 55.
    Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC et al (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394PubMedGoogle Scholar
  56. 56.
    Zhou M, Zhao Y, Ding Y et al (2010) Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer 9:33PubMedCrossRefGoogle Scholar
  57. 57.
    Basu A, Haldar S (1998) The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reprod 4:1099–1109PubMedCrossRefGoogle Scholar
  58. 58.
    Suzuki A, Shiraki K (2001) Tumor cell “dead or alive”: caspase and survivin regulate cell death, cell cycle and cell survival. Histol Histopathol 16:583–593PubMedGoogle Scholar
  59. 59.
    Suárez L, Vidriales B, García-Laraña J et al (2001) Multiparametric analysis of apoptotic and multi-drug resistance phenotypes according to the blast cell maturation stage in elderly patients with acute myeloid leukemia. Haematologica 86:1287–1295PubMedGoogle Scholar
  60. 60.
    Chauhan PS, Bhushan B, Singh LC et al (2012) Expression of genes related to multiple drug resistance and apoptosis in acute leukemia: response to induction chemotherapy. Exp Mol Pathol 92:44–49PubMedCrossRefGoogle Scholar
  61. 61.
    Guenova ML, Balatzenko GN, Nikolova VR, Spassov BV, Konstantinov SM (2010) An anti-apoptotic pattern correlates with multidrug resistance in acute myeloid leukemia patients: a comparative study of active caspase-3, cleaved PARPs, Bcl-2, Survivin and MDR1 gene. Hematology 15:135–143PubMedCrossRefGoogle Scholar
  62. 62.
    Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG (2002) The role of nitric oxide in cancer. Cell Res 12:311–320PubMedCrossRefGoogle Scholar
  63. 63.
    Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19:711–721PubMedCrossRefGoogle Scholar
  64. 64.
    Matthews NE, Adams MA, Maxwell LR, Gofton TE, Graham CH (2001) Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J Natl Cancer Inst 93:1879–1885PubMedCrossRefGoogle Scholar
  65. 65.
    Riganti C, Miraglia E, Viarisio D, Costamagna C, Pescarmona G, Ghigo D, Bosia A (2005) Nitric oxide reverts the resistance to doxorubicin in human colon cancer cells by inhibiting the drug efflux. Cancer Res 65:516–525PubMedGoogle Scholar
  66. 66.
    Nagata J, Kijima H, Hatanaka H et al (2001) Reversal of cisplatin and multidrug resistance by ribozyme-mediated glutathione suppression. Biochem Biophys Res Commun 286:406–413PubMedCrossRefGoogle Scholar
  67. 67.
    McWhinney SR, Goldberg RM, McLeod HL (2009) Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther 8:10–16PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.School of BiotechnologyBanaras Hindu UniversityVaranasiIndia

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