HIF-1α and RKIP: a computational approach for pancreatic cancer therapy

Abstract

Protein–protein interactions (PPIs) are important biochemical processes that represent a major challenge in modern biology. Current approaches, which include high-throughput screening and computer aided ligand design, have limitations regarding the identification of hit matter. This current investigation focuses on computational study for protein–protein docking of hypoxia inducible factor-1α (HIF-1α), a tumor inducible factor, and Raf-1 kinase inhibitory protein (RKIP), a tumor metastasis suppressor. These are individually crystallized structures of interacting proteins, which interact to generate a conformational space. HIF activity in pancreatic tumors is determined by hypoxia and HIF-1α subunit availability. RKIP can be used as a prognostic indicator in a number of tumors. The interaction of RKIP with HIF-1α protects against pancreatic cancer (PC) metastasis by inhibiting its hypoxia function. We have explored the binding affinity between both the proteins with the HADDOCK (high ambiguity driven protein–protein docking) server, which determined that 158 structures in 11 clusters represent 79.0% of water-refined models. Of the best 10 clusters, the structures of cluster 2 were found to be better, as they had the lowest Z-score. Further supporting HIF-1α-RKIP interaction, pulldown assay has shown dissociation of RKIP from HIF-1α after CoCl2 treatment in both PC cell lines.

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

Fig. 1
Fig. 2
Fig.3
Fig. 4
Fig. 5

Abbreviations

Akt:

Protein kinase B

AIRs:

Ambiguous interaction restraints

Au:

Arbitrary units

BSA:

Buried surface area

CASTp:

Computed atlas of surface topography of proteins

DNA:

Deoxyribonucleic acid

ERK:

Extracellular signal regulated kinase

FCC:

Fraction of common contacts

GPCR:

G protein-coupled receptor

HIF-1α:

Hypoxia inducible factor

HRE:

Hypoxia response elements

MAT2A:

Methionine adenosyltransferase

MAPK:

Mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

NF-қB:

Nuclear factor-kappa B

PC:

Pancreatic cancer

PEBP:

Phosphatidylethanolamine-binding protein

PDB:

Protein data bank

ProSA:

Protein structure analysis

PI3K:

Phosphoinositide3-kinases

QMEAN:

Qualitative model energy analysis

RCSB:

Research collaborator for structural bioinformatics

RKIP:

Raf kinase inhibitor protein

RMSD:

Root mean square deviation

SAM:

S-adenosylmethionine

TET:

Ten eleven translocation

VHL protein:

Von-Hippel–Lindau protein

References

  1. 1.

    Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70:7–30

    Article  Google Scholar 

  2. 2.

    Gupta MK, Sarojamma V, Reddy MR, Shaik JB, Vadde R (2019) Computational biology: toward early detection of pancreatic cancer. Crit Rev Oncogen 24(2):191–198

    Article  Google Scholar 

  3. 3.

    Nagaraju GP, Zakka KM, Landry JC, Shaib WL, Lesinski GB, El-Rayes BF (2019) Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer. Int J Cancer 145:1529–1537

    CAS  Article  Google Scholar 

  4. 4.

    Farran B, Nagaraju GP (2019) The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: novel therapeutic targets. Cytokine Growth Factor Rev 48:11–23

    CAS  Article  Google Scholar 

  5. 5.

    Nagaraju GP, Pattnaik S (2017) Hypoxia-inducible factor (HIF)-1α and its regulation in pancreatic cancer: role of transcription factors in gastrointestinal malignancies. Springer, New York, pp 371–378

    Google Scholar 

  6. 6.

    Bramhachari PV, Nagaraju GP (2017) Transcription factors in gastrointestinal malignancies: role of transcription factors in gastrointestinal malignancies. Springer, New York, pp 1–3

    Google Scholar 

  7. 7.

    Vadde R, Vemula S, Jinka R, Merchant N, Bramhachari PV, Nagaraju GP (2017) Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer. Crit Rev Oncol/Hematol 113:22–27

    Article  Google Scholar 

  8. 8.

    Momin S, Nagaraju GP (2019) The role of hypoxia inducible factor-1α in pancreatic cancer and diabetes mellitus. Exploring pancreatic metabolism and malignancy. Springer, New York, pp 173–181

    Google Scholar 

  9. 9.

    Camuzi D, de Amorim ÍSS, Ribeiro Pinto LF, Oliveira Trivilin L, Mencalha AL, Soares Lima SC (2019) Regulation is in the air: the relationship between hypoxia and epigenetics in cancer. Cells 8:300

    CAS  Article  Google Scholar 

  10. 10.

    Liu Q, Liu L, Zhao Y, Zhang J, Wang D, Chen J, He Y, Wu J, Zhang Z, Liu Z (2011) Hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells. Mol Cancer Ther 10:1113–1123

    CAS  Article  Google Scholar 

  11. 11.

    Dariya B, Chalikonda G, Alam A, Nagaraju GP (2020) Theranostic role of RKIP in cancer. Prognostic and therapeutic applications of RKIP in cancer. Elsevier, New York, pp 415–434

    Google Scholar 

  12. 12.

    Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W (2000) Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol 20:3079–3085. https://doi.org/10.1128/mcb.20.9.3079-3085.2000

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Baritaki S, Katsman A, Chatterjee D, Yeung KC, Spandidos DA, Bonavida B (2007) Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic suppressor Raf kinase inhibitor protein via Yin Yang 1 inhibition and death receptor 5 up-regulation. J Immunol 179:5441–5453

    CAS  Article  Google Scholar 

  14. 14.

    Wang Y, Bonavida B (2020) Pleiotropic activities of RKIP in cancer: role in survival, EMT, chemo-immuno-resistance, and autophagy. Prognostic and therapeutic applications of RKIP in cncer. Elsevier, New York, pp 47–75

    Google Scholar 

  15. 15.

    Gupta MK, Vadde R (2019) In silico identification of natural product inhibitors for γ-secretase activating protein, a therapeutic target for Alzheimer’s disease. J Cell Biochem 120:10323–10336

    CAS  Article  Google Scholar 

  16. 16.

    Wallner B, Fang H, Elofsson A (2003) Automatic consensus-based fold recognition using Pcons, ProQ, and Pmodeller. Proteins Struct Funct Bioinform 53:534–541

    CAS  Article  Google Scholar 

  17. 17.

    Benkert P, Tosatto SC, Schomburg D (2008) QMEAN: a comprehensive scoring function for model quality assessment. Proteins Struct Funct Bioinform 71:261–277

    CAS  Article  Google Scholar 

  18. 18.

    Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35:W407–W410

    Article  Google Scholar 

  19. 19.

    Dominguez C, Boelens R, Bonvin AM (2003) HADDOCK: a protein−protein docking approach based on biochemical or biophysical information. J Am Chem Soc 125:1731–1737

    CAS  Article  Google Scholar 

  20. 20.

    Nagaraju GP, Zhu S, Wen J, Farris AB, Adsay VN, Diaz R, Snyder JP, Mamoru S, El-Rayes BF (2013) Novel synthetic curcumin analogues EF31 and UBS109 are potent DNA hypomethylating agents in pancreatic cancer. Cancer Lett 341:195–203

    CAS  Article  Google Scholar 

  21. 21.

    Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5:378–389. https://doi.org/10.1016/j.apsb.2015.05.007

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Polireddy K, Chen Q (2016) Cancer of the pancreas: molecular pathways and current advancement in treatment. J Cancer 7:1497

    CAS  Article  Google Scholar 

  23. 23.

    Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G (2004) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Can Res 64:1475–1482

    CAS  Article  Google Scholar 

  24. 24.

    Jiang B-H, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK (2001) Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ 12:363–370

    CAS  PubMed  Google Scholar 

  25. 25.

    Osada M, Imaoka S, Funae Y (2004) Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1α protein. FEBS Lett 575:59–63

    CAS  Article  Google Scholar 

  26. 26.

    Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL (2009) Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci 106:17910–17915

    CAS  Article  Google Scholar 

  27. 27.

    Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Can Res 65:9047–9055

    CAS  Article  Google Scholar 

  28. 28.

    Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6:33–43

    CAS  Article  Google Scholar 

  29. 29.

    Goda AE, Erikson RL, Sakai T, Ahn J-S, Kim B-Y (2015) Preclinical evaluation of bortezomib/dipyridamole novel combination as a potential therapeutic modality for hematologic malignancies. Mol Oncol 9:309–322

    CAS  Article  Google Scholar 

  30. 30.

    Yu T, Tang B, Sun X (2017) Development of inhibitors targeting hypoxia-inducible factor 1 and 2 for cancer therapy. Yonsei Med J 58:489–496. https://doi.org/10.3349/ymj.2017.58.3.489

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ling HH, Mendoza-Viveros L, Mehta N, Cheng H-YM (2014) Raf kinase inhibitory protein (RKIP): functional pleiotropy in the mammalian brain. Crit Rev Oncogen 19:505–516

    Article  Google Scholar 

  32. 32.

    Al-Mulla F, Bitar MS, Taqi Z, Yeung KC (2013) RKIP: much more than Raf kinase inhibitory protein. J Cell Physiol 228:1688–1702

    CAS  Article  Google Scholar 

  33. 33.

    Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H (1999) Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401:173

    CAS  Article  Google Scholar 

  34. 34.

    Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5:378–389. https://doi.org/10.1016/j.apsb.2015.05.007

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (1997) Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci USA 94:5667–5672. https://doi.org/10.1073/pnas.94.11.5667

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Trakul N, Menard RE, Schade GR, Qian Z, Rosner MR (2005) Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. J Biol Chem 280:24931–24940

    CAS  Article  Google Scholar 

  37. 37.

    King AJ, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S, Marshall MS (1998) The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396:180

    CAS  Article  Google Scholar 

  38. 38.

    Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R (1999) Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 18:2137–2148

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

GS contributed in guarantor of integrity of the entire study; AA and GP contributed in study design; GS contributed in definition of intellectual content; BD and GC contributed in literature research; GS contributed in experimental studies; SB and GS contributed in data acquisition and analysis; AA and GP contributed in manuscript preparation; GP contributed in manuscript editing; AA and GP contributed in manuscript review. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ganji Purnachandra Nagaraju.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Srivani, G., Behera, S.K., Dariya, B. et al. HIF-1α and RKIP: a computational approach for pancreatic cancer therapy. Mol Cell Biochem (2020). https://doi.org/10.1007/s11010-020-03788-6

Download citation

Keywords

  • Cluster
  • HADDOCK
  • HIF-1α
  • Interaction
  • Pancreatic cancer
  • RKIP