Skip to main content

Advertisement

SpringerLink
Log in

Combinatorial treatment with anacardic acid followed by TRAIL augments induction of apoptosis in TRAIL resistant cancer cells by the regulation of p53, MAPK and NFκβ pathways

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

TRAIL, an apoptosis inducing cytokine currently in phase II clinical trial, was investigated for its capability to induce apoptosis in six different human tumor cell lines out of which three cell lines showed resistance to TRAIL induced apoptosis. To investigate whether Anacardic acid (A1) an active component of Anacardium occidentale can sensitize the resistant cell lines to TRAIL induced apoptosis, we treated the resistant cells with suboptimal concentration of A1 and showed that it is a potent enhancer of TRAIL induced apoptosis which up-regulates the expression of both DR4 and DR5 receptors, which has been observed in the cellular, protein and mRNA levels. The death receptors upregulation consequent to A1 treatment was corroborated by the activation of p53 as well as phosphorylation of p38 and JNK MAP kinases and concomitant inactivation of NFκβ and ERK signaling cascades. Also, A1 modulated the expression of key apoptotic players like Bax, Bcl-2 and CAD along with the abatement of tumor angiogenesis in vivo in EAT mouse model. Thus, post A1 treatment the TRAIL resistant cells turned into TRAIL sensitive cells. Hence our results demonstrate that A1 can synergize TRAIL induced apoptosis through the upregulation of death receptors and downregulation of anti-apoptotic proteins in cancer context.

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

Similar content being viewed by others

Abbreviations

A1:

Anacardic acid

TRAIL:

TNFα related apoptosis inducing ligand

DRs:

Death receptors

DR4, DR5:

Death receptor 4 and 5

DcR1, DcR2:

Decoy receptor 1 and 2

FasL:

FAS ligand

TNFα:

Tumor necrosis factor α

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2 protein

Cad:

Caspase activated DNase

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer. GLOBOCAN 2008

  2. Bonavida B, Khineche S, Huerta-Yepez S, Garbán H (2006) Therapeutic potential of nitric oxide in cancer. Drug Resist Updates 9(3):157–173

    Article  CAS  Google Scholar 

  3. Almasan A, Ashkenazi A (2003) Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 14(3):337–348

    Article  CAS  PubMed  Google Scholar 

  4. Ashkenazi A, Pai R, Fong S, Leung S, Lawrence D, Marsters S et al (1999) Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Investig 104(2):155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang L, Fang B (2005) Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12(3):228–237

    Article  CAS  PubMed  Google Scholar 

  6. Arizono Y, Yoshikawa H, Naganuma H, Hamada Y, Nakajima Y, Tasaka K (2003) A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents. Br J Cancer 88(2):298–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kimberley FC, Screaton GR (2004) Following a TRAIL: update on a ligand and its five receptors. Cell Res 14(5):359–372

    Article  CAS  PubMed  Google Scholar 

  8. Griffith TS, Lynch DH (1998) TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 10(5):559–563

    Article  CAS  PubMed  Google Scholar 

  9. Thome M, Schneider P, Hofmann K, Fickenscher H, Meini E, Neipel F et al (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386(6624):517–521

    Article  CAS  PubMed  Google Scholar 

  10. Dan’ura T, Kawai A, Morimoto Y, Naito N, Yoshida A, Inoue H (2002) Apoptosis and expression of its regulatory proteins in soft tissue sarcomas. Cancer Lett 178(2):167–174

    Article  PubMed  Google Scholar 

  11. Jung E, Lim J, Lee T, Park J, Choi K, Kwon T (2005) Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis 26(11):1905–1913

    Article  CAS  PubMed  Google Scholar 

  12. Shenoy K, Wu Y, Pervaiz S (2009) LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide–mediated mitogen-activated protein kinase activation and up-regulation of death receptors. Cancer Res 69(5):1941–1950

    Article  CAS  PubMed  Google Scholar 

  13. Prasad S, Yadav V, Kannappan R, Aggarwal B (2011) Ursolic acid, a pentacyclin triterpene, potentiates TRAIL-induced apoptosis through p53-independent Up-regulation of death receptors evidence for the role of reactive oxygen species and JNK. J Biol Chem 286(7):5546–5557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maksimovic-Ivanic D, Stosic-Grujicic S, Nicoletti F, Mijatovic S (2012) Resistance to TRAIL and how to surmount it. Immunol Res 52(1–2):157–168

    Article  CAS  PubMed  Google Scholar 

  15. Tsai WS, Yeow WS, Chua A, Reddy RM, Nguyen DM, Schrump DS et al (2006) Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin. Mol Cancer Ther 5(12):2977–2990

    Article  CAS  PubMed  Google Scholar 

  16. Kim SH, Ricci MS, El-Deiry WS (2008) Mcl-1: a gateway to TRAIL sensitization. Cancer Res 68(7):2062–2064

    Article  CAS  PubMed  Google Scholar 

  17. Kim M, Liao J, Dowling M, Voong KR, Parker SE, Wang S et al (2008) TRAIL inactivates the mitotic checkpoint and potentiates death induced by microtubule-targeting agents in human cancer cells. Cancer Res 68(9):3440–3449

    Article  CAS  PubMed  Google Scholar 

  18. Sung B, Pandey MK, Ahn KS, Yi T, Chaturvedi MM, Liu M et al (2008) Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB–regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis. Blood 111(10):4880–4891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hemshekhar M, Sebastin SM, Kemparaju K, Girish KS (2012) Emerging roles of anacardic acid and its derivatives: a pharmacological overview. Basic Clin Pharmacol Toxicol 110(2):122–132

    Article  CAS  PubMed  Google Scholar 

  20. Tan J, Chen B, He L, Tang Y, Jiang Z, Yin G et al (2012) Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer cells through inhibition of androgen receptor and activation of p53 signaling. Chin J Cancer Res 24(4):275–283

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shilpa P, Kaveri K, Salimath BP (2015) Anti-metastatic action of anacardic acid targets VEGF-induced signalling pathways in epithelial to mesenchymal transition. Drug Discov Ther 9(1):53–65

    Article  PubMed  Google Scholar 

  22. Gantert M, Lewrick F, Adrian JE, Rössler J, Steenpaß T, Schubert R et al (2009) Receptor-specific targeting with liposomes in vitro based on sterol-PEG1300 anchors. Pharm Res 26(3):529–538

    Article  CAS  PubMed  Google Scholar 

  23. Zeng H, Sanyal S, Mukhopadhyay D (2001) Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively. J Biol Chem 276(35):32714–32719

    Article  CAS  PubMed  Google Scholar 

  24. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  25. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM (1997) An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277(5327):815–818

    Article  CAS  PubMed  Google Scholar 

  26. Sheridan JP, Marsters SA, Pitt RM, Gurney A, Skubatch M, Baldwin D et al (1997) Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277(5327):818–821

    Article  CAS  PubMed  Google Scholar 

  27. Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2(4):277–288

    Article  CAS  PubMed  Google Scholar 

  28. Lauricella M, Ciraolo A, Carlisi D, Vento R, Tesoriere G (2012) SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells. Biochimie 94(2):287–299

    Article  CAS  PubMed  Google Scholar 

  29. Kahana S, Finniss S, Cazacu S, Xiang C, Lee H, Brodie S et al (2011) Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions. Cell Signal 23(8):1348–1357

    Article  CAS  PubMed  Google Scholar 

  30. Pellerito O, Calvaruso G, Portanova P, De Blasio A, Santulli A, Vento R et al (2010) The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating p8/CCAAT/enhancer binding protein homologous protein (CHOP)/death receptor 5 (DR5) axis. Mol Pharmacol 77(5):854–863

    Article  CAS  PubMed  Google Scholar 

  31. Hamad FB, Mubofu EB (2015) Potential biological applications of bio-based anacardic acids and their derivatives. Int J Mol Sci 16(4):8569–8590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ (2007) Targeting death-inducing receptors in cancer therapy. Oncogene 26(25):3745–3757

    Article  CAS  PubMed  Google Scholar 

  33. Sung B, Ravindran J, Prasad S, Pandey MK, Aggarwal BB (2010) Gossypol induces death receptor-5 through activation of the ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. J Biol Chem 285(46):35418–35427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu X, Yue P, Khuri FR, Sun S (2004) p53 upregulates death receptor 4 expression through an intronic p53 binding site. Cancer Res 64(15):5078–5083

    Article  CAS  PubMed  Google Scholar 

  35. Wu GS, Burns TF, McDonald ER 3rd, Jiang W, Meng R, Krantz ID et al (1997) KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17(2):141

    Article  CAS  PubMed  Google Scholar 

  36. Sun S, Yue P, Hong WK, Lotan R (2000) Augmentation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) through up-regulation of TRAIL receptors in human lung cancer cells. Cancer Res 60(24):7149–7155

    CAS  PubMed  Google Scholar 

  37. Sheikh MS, Burns TF, Huang Y, Wu GS, Amundson S, Brooks KS et al (1998) p53-dependent and-independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor α. Cancer Res 58(8):1593–1598

    CAS  PubMed  Google Scholar 

  38. Azijli K, Yuvaraj S, van Roosmalen I, Flach K, Giovannetti E, Peters GJ et al (2013) MAPK p38 and JNK have opposing activities on TRAIL-induced apoptosis activation in NSCLC H460 cells that involves RIP1 and caspase-8 and is mediated by Mcl-1. Apoptosis 18(7):851–860

    Article  CAS  PubMed  Google Scholar 

  39. Cheng H, Hong B, Zhou L, Allen JE, Tai G, Humphreys R et al (2012) Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: Evidence for the role of c-Jun N-terminal kinase activation. Cell Cycle 11(17):3312–3323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kang C, Moon D, Choi YH, Choi I, Moon S, Kim WJ et al (2011) Piceatannol enhances TRAIL-induced apoptosis in human leukemia THP-1 cells through Sp1-and ERK-dependent DR5 up-regulation. Toxicol In Vitro 25(3):605–612

    Article  CAS  PubMed  Google Scholar 

  41. Lepage C, Léger DY, Bertrand J, Martin F, Beneytout JL, Liagre B (2011) Diosgenin induces death receptor-5 through activation of p38 pathway and promotes TRAIL-induced apoptosis in colon cancer cells. Cancer Lett 301(2):193–202

    Article  CAS  PubMed  Google Scholar 

  42. Krishna M, Narang H (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 65(22):3525–3544

    Article  CAS  PubMed  Google Scholar 

  43. Fulda S, Wick W, Weller M, Debatin KM (2002) Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8(8):808–815

    CAS  PubMed  Google Scholar 

  44. Ravi R, Bedi A (2002) Sensitization of tumor cells to Apo2 ligand/TRAIL-induced apoptosis by inhibition of casein kinase II. Cancer Res 62(15):4180–4185

    CAS  PubMed  Google Scholar 

  45. Kruyt FA (2008) TRAIL and cancer therapy. Cancer Lett 263(1):14–25

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge funding by Department of Biotechnology, New Delhi, India, BT/IN/German/06/BPS/2010 and BMBF-IND 10/026, to BPS and JR respectively, University Grants Commission-Government of India No. f 4-1/2013SAP II and f.No. 14/4/2012(NS/PE). The discussions and help given by Prof. Dr. Regine Süss and Dr. V. Rengaswamy for liposome studies is acknowledged.

Author information

Authors and Affiliations

  1. Molecular Oncology Lab, Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore, Karnataka, 570 006, India

    M. Harsha Raj, B. Yashaswini & Bharathi P. Salimath

  2. Clinic IV: Pediatric Hematology and Oncology, Center of Pediatrics and Adolescent Medicine, University Medical Hospital, Mathildenstrasse 1, 79106, Freiburg, Germany

    Jochen Rössler

Authors
  1. M. Harsha Raj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Yashaswini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jochen Rössler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bharathi P. Salimath
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bharathi P. Salimath.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10495_2016_1223_MOESM1_ESM.tif

Supplementary material 1 (TIFF 2773 kb) Sup Fig. 1 (a) Liposome size was determined by dynamic light scattering using a zeta potential/particle sizer of freshly prepared liposomes was performed by diluting in isotonic HBS buffer. (b) In vitro cytotoxicity of A1-liposome formulation and free drug A1 (100 µg) on 8 human tumor cell lines: 5x104 cells were seeded in 46 well plates and treated with A1-liposome formulation, A1 alone, free liposomes and untreated cells for 12 h. The cytotoxicity was assessed by trypan blue dye exclusion method

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Harsha Raj, M., Yashaswini, B., Rössler, J. et al. Combinatorial treatment with anacardic acid followed by TRAIL augments induction of apoptosis in TRAIL resistant cancer cells by the regulation of p53, MAPK and NFκβ pathways. Apoptosis 21, 578–593 (2016). https://doi.org/10.1007/s10495-016-1223-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-016-1223-8

Keywords

Search

Navigation