Skip to main content

Advertisement

SpringerLink
Log in

Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Bitter taste receptors (Tas2Rs) are a subfamily of G-protein coupled receptors expressed not only in the oral cavity but also in several extra-oral tissues and disease states. Several natural bitter compounds from plants, such as bitter melon extract and noscapine, have displayed anti-cancer effects against various cancer types. In this study, we examined the prevalence of Tas2R subtype expression in several epithelial ovarian or prostate cancer cell lines, and the functionality of Tas2R14 was determined. qPCR analysis of five TAS2Rs demonstrated that mRNA expression often varies greatly in cancer cells in comparison to normal tissue. Using receptor-specific siRNAs, we also demonstrated that noscapine stimulation of ovarian cancer cells increased apoptosis in ovarian cancer cells in a receptor-dependent, but ROS-independent manner. This study furthers our understanding of the function of Tas2Rs in ovarian cancer by demonstrating that their activation has an impact on cell survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Li D, Zhang J (2014) Diet shapes the evolution of the vertebrate bitter taste receptor gene repertoire. Mol Biol Evol 31:303–309. https://doi.org/10.1093/molbev/mst219

    Article  CAS  PubMed  Google Scholar 

  2. Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ (2000) T2Rs function as bitter taste receptors. Cell 100:703–711

    Article  CAS  PubMed  Google Scholar 

  3. Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, Liggett SB (2010) Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med 16:1299–1304. https://doi.org/10.1038/nm.2237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Deloose E, Janssen P, Corsetti M, Biesiekierski J, Masuy I, Rotondo A, Van Oudenhove L, Depoortere I, Tack J (2017) Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers. Am J Clin Nutr 105:580–588. https://doi.org/10.3945/ajcn.116.138297

    Article  CAS  PubMed  Google Scholar 

  5. Foster SR, Porrello ER, Purdue B, Chan HW, Voigt A, Frenzel S, Hannan RD, Moritz KM, Simmons DG, Molenaar P, Roura E, Boehm U, Meyerhof W, Thomas WG (2013) Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart. PLoS ONE 8:e64579. https://doi.org/10.1371/journal.pone.0064579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Singh N, Vrontakis M, Parkinson F, Chelikani P (2011) Functional bitter taste receptors are expressed in brain cells. Biochem Biophys Res Commun 406:146–151. https://doi.org/10.1016/j.bbrc.2011.02.016

    Article  CAS  PubMed  Google Scholar 

  7. Li F (2013) Taste perception: from the tongue to the testis. Mol Hum Reprod 19:349–360. https://doi.org/10.1093/molehr/gat009

    Article  CAS  PubMed  Google Scholar 

  8. Clark AA, Dotson CD, Elson AE, Voigt A, Boehm U, Meyerhof W, Steinle NI, Munger SD (2015) TAS2R bitter taste receptors regulate thyroid function. FASEB J 29:164–172. https://doi.org/10.1096/fj.14-262246

    Article  CAS  PubMed  Google Scholar 

  9. Ansoleaga B, Garcia-Esparcia P, Pinacho R, Haro JM, Ramos B, Ferrer I (2015) Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia. J Psychiatr Res 60:109–116. https://doi.org/10.1016/j.jpsychires.2014.09.012

    Article  PubMed  Google Scholar 

  10. Garcia-Esparcia P, Schluter A, Carmona M, Moreno J, Ansoleaga B, Torrejon-Escribano B, Gustincich S, Pujol A, Ferrer I (2013) Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. J Neuropathol Exp Neurol 72:524–539. https://doi.org/10.1097/NEN.0b013e318294fd76

    Article  CAS  PubMed  Google Scholar 

  11. Lu P, Zhang CH, Lifshitz LM, ZhuGe R (2017) Extraoral bitter taste receptors in health and disease. J Gen Physiol 149:181–197. https://doi.org/10.1085/jgp.201611637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Singh N, Chakraborty R, Bhullar RP, Chelikani P (2014) Differential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells. Biochem Biophys Res Commun 446:499–503. https://doi.org/10.1016/j.bbrc.2014.02.140

    Article  CAS  PubMed  Google Scholar 

  13. Gaida MM, Mayer C, Dapunt U, Stegmaier S, Schirmacher P, Wabnitz GH, Hansch GM (2016) Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget 7:12623–12632. https://doi.org/10.18632/oncotarget.7206

    Article  PubMed  PubMed Central  Google Scholar 

  14. Doddapaneni R, Patel K, Chowdhury N, Singh M (2016) Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer. Exp Cell Res 346:65–73. https://doi.org/10.1016/j.yexcr.2016.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917. https://doi.org/10.1002/ijc.25516

    Article  CAS  PubMed  Google Scholar 

  16. Bax HJ, Josephs DH, Pellizzari G, Spicer JF, Montes A, Karagiannis SN (2016) Therapeutic targets and new directions for antibodies developed for ovarian cancer. MAbs 8:1437–1455. https://doi.org/10.1080/19420862.2016.1219005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yung MM, Ross FA, Hardie DG, Leung TH, Zhan J, Ngan HY, Chan DW (2016) Bitter Melon (Momordica charantia) extract inhibits tumorigenicity and overcomes cisplatin-resistance in ovarian cancer cells through targeting AMPK signaling cascade. Integr Cancer Ther 15:376–389. https://doi.org/10.1177/1534735415611747

    Article  CAS  PubMed  Google Scholar 

  18. Kwatra D, Subramaniam D, Ramamoorthy P, Standing D, Moran E, Velayutham R, Mitra A, Umar S, Anant S (2013) Methanolic extracts of bitter melon inhibit colon cancer stem cells by affecting energy homeostasis and autophagy. Evid Based Complement Alternat Med 2013:702869. https://doi.org/10.1155/2013/702869

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kwatra D, Venugopal A, Standing D, Ponnurangam S, Dhar A, Mitra A, Anant S (2013) Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance. J Pharm Sci 102:4444–4454. https://doi.org/10.1002/jps.23753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ru P, Steele R, Nerurkar PV, Phillips N, Ray RB (2011) Bitter melon extract impairs prostate cancer cell-cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model. Cancer Prev Res (Phila) 4:2122–2130. https://doi.org/10.1158/1940-6207.CAPR-11-0376

    Article  Google Scholar 

  21. Ray RB, Raychoudhuri A, Steele R, Nerurkar P (2010) Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Cancer Res 70:1925–1931. https://doi.org/10.1158/0008-5472.CAN-09-3438

    Article  CAS  PubMed  Google Scholar 

  22. Shen W, Liang B, Yin J, Li X, Cheng J (2015) noscapine increases the sensitivity of drug-resistant ovarian cancer cell line SKOV3/DDP to cisplatin by regulating cell cycle and activating apoptotic pathways. Cell Biochem Biophys 72:203–213. https://doi.org/10.1007/s12013-014-0438-y

    Article  CAS  PubMed  Google Scholar 

  23. Barken I, Geller J, Rogosnitzky M (2008) Noscapine inhibits human prostate cancer progression and metastasis in a mouse model. Anticancer Res 28:3701–3704

    CAS  PubMed  Google Scholar 

  24. Aneja R, Vangapandu SN, Lopus M, Chandra R, Panda D, Joshi HC (2006) Development of a novel nitro-derivative of noscapine for the potential treatment of drug-resistant ovarian cancer and T-cell lymphoma. Mol Pharmacol 69:1801–1809. https://doi.org/10.1124/mol.105.021899

    Article  CAS  PubMed  Google Scholar 

  25. Su W, Huang L, Ao Q, Zhang Q, Tian X, Fang Y, Lu Y (2011) Noscapine sensitizes chemoresistant ovarian cancer cells to cisplatin through inhibition of HIF-1alpha. Cancer Lett 305:94–99. https://doi.org/10.1016/j.canlet.2011.02.031

    Article  CAS  PubMed  Google Scholar 

  26. Jaggupilli A, Singh N, Upadhyaya J, Sikarwar AS, Arakawa M, Dakshinamurti S, Bhullar RP, Duan K, Chelikani P (2017) Analysis of the expression of human bitter taste receptors in extraoral tissues. Mol Cell Biochem 426:137–147. https://doi.org/10.1007/s11010-016-2902-z

    Article  CAS  PubMed  Google Scholar 

  27. Shaik FA, Singh N, Arakawa M, Duan K, Bhullar RP, Chelikani P (2016) Bitter taste receptors: extraoral roles in pathophysiology. Int J Biochem Cell Biol doi. https://doi.org/10.1016/j.biocel.2016.03.011

    Article  Google Scholar 

  28. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    Article  CAS  Google Scholar 

  29. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  30. Young B, Purcell C, Kuang YQ, Charette N, Dupre DJ (2015) Superoxide dismutase 1 regulation of CXCR4-mediated signaling in prostate cancer cells is dependent on cellular oxidative state. Cell Physiol Biochem 37:2071–2084. https://doi.org/10.1159/000438566

    Article  CAS  PubMed  Google Scholar 

  31. Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC Jr, Beral V, Berek JS, Birrer MJ, Blagden S, Bookman MA, Brenton JD, Chiappinelli KB, Martins FC, Coukos G, Drapkin R, Edmondson R, Fotopoulou C, Gabra H, Galon J, Gourley C, Heong V, Huntsman DG, Iwanicki M, Karlan BY, Kaye A, Lengyel E, Levine DA, Lu KH, McNeish IA, Menon U, Narod SA, Nelson BH, Nephew KP, Pharoah P, Powell DJ Jr, Ramos P, Romero IL, Scott CL, Sood AK, Stronach EA, Balkwill FR (2015) Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 15:668–679. https://doi.org/10.1038/nrc4019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kurman RJ, Shih Ie M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34:433–443. https://doi.org/10.1097/PAS.0b013e3181cf3d79

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhou J, Gupta K, Yao J, Ye K, Panda D, Giannakakou P, Joshi HC (2002) Paclitaxel-resistant human ovarian cancer cells undergo c-Jun NH2-terminal kinase-mediated apoptosis in response to noscapine. J Biol Chem 277:39777–39785. https://doi.org/10.1074/jbc.M203927200

    Article  CAS  PubMed  Google Scholar 

  34. Rida PC, LiVecche D, Ogden A, Zhou J, Aneja R (2015) The noscapine chronicle: a pharmaco-historic biography of the opiate alkaloid family and its clinical applications. Med Res Rev 35:1072–1096. https://doi.org/10.1002/med.21357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sung B, Ahn KS, Aggarwal BB (2010) Noscapine, a benzylisoquinoline alkaloid, sensitizes leukemic cells to chemotherapeutic agents and cytokines by modulating the NF-kappaB signaling pathway. Cancer Res 70:3259–3268. https://doi.org/10.1158/0008-5472.CAN-09-4230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chougule M, Patel AR, Sachdeva P, Jackson T, Singh M (2011) Anticancer activity of Noscapine, an opioid alkaloid in combination with Cisplatin in human non-small cell lung cancer. Lung Cancer 71:271–282. https://doi.org/10.1016/j.lungcan.2010.06.002

    Article  PubMed  Google Scholar 

  37. Chougule MB, Patel AR, Jackson T, Singh M (2011) Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer. PLoS One 6:e17733. https://doi.org/10.1371/journal.pone.0017733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chougule MB, Patel A, Sachdeva P, Jackson T, Singh M (2011) Enhanced anticancer activity of gemcitabine in combination with noscapine via antiangiogenic and apoptotic pathway against non-small cell lung cancer. PLoS One 6:e27394. https://doi.org/10.1371/journal.pone.0027394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aneja R, Dhiman N, Idnani J, Awasthi A, Arora SK, Chandra R, Joshi HC (2007) Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent. Cancer Chemother Pharmacol 60:831–839. https://doi.org/10.1007/s00280-007-0430-y

    Article  CAS  PubMed  Google Scholar 

  40. Carrai M, Steinke V, Vodicka P, Pardini B, Rahner N, Holinski-Feder E, Morak M, Schackert HK, Gorgens H, Stemmler S, Betz B, Kloor M, Engel C, Buttner R, Naccarati A, Vodickova L, Novotny J, Stein A, Hemminki K, Propping P, Forsti A, Canzian F, Barale R, Campa D (2011) Association between TAS2R38 gene polymorphisms and colorectal cancer risk: a case-control study in two independent populations of Caucasian origin. PLoS One 6:e20464. https://doi.org/10.1371/journal.pone.0020464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by Grant funding from the Natural Sciences and Engineering Research Council of Canada (NSERC) (Grant RGPIN-355310-2013) and seed funding from the Beatrice Hunter Cancer Research Institute (BHCRI) (to DJD), a Bridge Grant from BHCRI (to GD), and a CancerCare Manitoba Foundation grant (to MWN). LTPM is supported through a Canadian Graduate Scholarship from the Canadian Institutes of Health Research and is a trainee in the Cancer Research Training Program of the BHCRI, with funds provided by Motorcycle Ride for Dad—Nova Scotia Chapter. JS was supported by a postdoctoral fellowship from the BHCRI.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada

    Louis T. P. Martin, Tamara Selman, Elaine Nguyen & Denis J. Dupré

  2. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada

    Mark W. Nachtigal

  3. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Manitoba, Winnipeg, MB, Canada

    Mark W. Nachtigal

  4. CancerCare Manitoba Research Institute, CancerCare MB, Winnipeg, MB, Canada

    Mark W. Nachtigal

  5. Department of Pathology, Dalhousie University, Halifax, NS, Canada

    Jayme Salsman & Graham Dellaire

  6. Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada

    Graham Dellaire

  7. Beatrice Hunter Cancer Research Institute, Halifax, Canada

    Graham Dellaire & Denis J. Dupré

  8. Department of Pharmacology, Faculty of medicine, Sir Charles Tupper Medical Building, Room 6C, 5850 College St, PO BOX 15 000, B3H 4R2, Halifax, NS, Canada

    Denis J. Dupré

Authors
  1. Louis T. P. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark W. Nachtigal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tamara Selman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elaine Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jayme Salsman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Graham Dellaire
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Denis J. Dupré
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Denis J. Dupré.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin, L.T.P., Nachtigal, M.W., Selman, T. et al. Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival. Mol Cell Biochem 454, 203–214 (2019). https://doi.org/10.1007/s11010-018-3464-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3464-z

Keywords

Search

Navigation