Investigational New Drugs

, Volume 37, Issue 2, pp 252–261 | Cite as

Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types

  • Cijo George Vazhappilly
  • Ekram Saleh
  • Wafaa Ramadan
  • Varsha Menon
  • Aya Mudhafar Al-Azawi
  • Hamadeh Tarazi
  • Hajjaj Abdu-Allah
  • Abdel-Nasser El-Shorbagi
  • Raafat El-AwadyEmail author


Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate–4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2. An enzymatic assay confirmed the docking results whereby 0.01 μM of both compounds reduced SHP2 activity to 50%. On cellular level, the two compounds significantly reduced the expression of SHP2, KRAS, p-ERK and p-STAT3 in HeLa but not in the other two cell lines. Phosphorylation of AKT and JNK was enhanced in HeLa and MCF7. Both compounds exhibited anti-proliferative/anti-migratory effects on HeLa and MCF7 but not in MDA-MB-231 cells. These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types.


SHP2 RAS/MAPK AKT STAT3 Phosphatase inhibitors 



The work was supported by AlJalila Foundation for Medical Education and Research, United Arab Emirates [grant number. AJF201612]

Compliance with Ethical Standards

Conflict of Interest

Author CV declares that he has no conflict of interest. Author ES declares that he has no conflict of interest. Author WR declares that he has no conflict of interest. Author VM declares that he has no conflict of interest. Author AA declares that he has no conflict of interest. Author HT declares that he has no conflict of interest. Author HA declares that he has no conflict of interest. Author AE declares that he has no conflict of interest. Author RE declares that he has no conflict of interest

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.


  1. 1.
    Ventura J-J, Nebreda AR (2006) Protein kinases and phosphatases as therapeutic targets in cancer. Clin Transl Oncol 8:153–160. CrossRefGoogle Scholar
  2. 2.
    Zhang J, Zhang F, Niu R (2015) Functions of Shp2 in cancer. J Cell Mol Med 19:2075–2083. CrossRefGoogle Scholar
  3. 3.
    Zhao S, Sedwick D, Wang Z (2014) Genetic alterations of protein tyrosine phosphatases in human cancers. Oncogene:1–10.
  4. 4.
    Han T, Xiang D-M, Sun W, Liu N, Sun H-L, Wen W, Shen W-F, Wang R-Y, Chen C, Wang X, Cheng Z, Li H-Y, Wu M-C, Cong W-M, Feng G-S, Ding J, Wang H-Y (2015) PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients. J Hepatol 63.
  5. 5.
    Grossmann KS, Rosário M, Birchmeier C, Birchmeier W (2010) The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 106:53–89. CrossRefGoogle Scholar
  6. 6.
    Zhou XD, Agazie YM (2008) Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ 15:988–996. CrossRefGoogle Scholar
  7. 7.
    Dance M, Montagner A, Salles JP, Yart A, Raynal P (2008) The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal 20:453–459. CrossRefGoogle Scholar
  8. 8.
    Butterworth S, Overduin M, Barr AJ (2014) Targeting protein tyrosine phosphatase SHP2 for therapeutic intervention. Future Med Chem 6:1423–1437. CrossRefGoogle Scholar
  9. 9.
    Liu Z, Zhao Y, Fang J, Cui R, Xiao Y, Xu Q, Liu Z, Zhao Y, Fang J, Cui R, Xiao Y, Xu Q (2017) SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells. Oncotarget 8:53518–53530. Google Scholar
  10. 10.
    Aceto N, Sausgruber N, Brinkhaus H, Gaidatzis D, Martiny-Baron G, Mazzarol G, Confalonieri S, Quarto M, Hu G, Balwierz PJ, Pachkov M, Elledge SJ, van Nimwegen E, Stadler MB, Bentires-Alj M (2012) Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop. Nat Med 18:529–537. CrossRefGoogle Scholar
  11. 11.
    Wu D, Pang Y, Ke Y, Yu J, He Z, Tautz L, Mustelin T, Ding S, Huang Z, Feng GS (2009) A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by Shp2 tyrosine phosphatase. PLoS One 4.
  12. 12.
    Chen Y-NP, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, Antonakos B, Chen CH-T, Chen Z, Cooke VG, Dobson JR, Deng Z, Fei F, Firestone B, Fodor M, Fridrich C, Gao H, Grunenfelder D, Hao H-X, Jacob J, Ho S, Hsiao K, Kang ZB, Karki R, Kato M, Larrow J, La Bonte LR, Lenoir F, Liu G, Liu S, Majumdar D, Meyer MJ, Palermo M, Perez L, Pu M, Price E, Quinn C, Shakya S, Shultz MD, Slisz J, Venkatesan K, Wang P, Warmuth M, Williams S, Yang G, Yuan J, Zhang J-H, Zhu P, Ramsey T, Keen NJ, Sellers WR, Stams T, Fortin PD (2016) Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535:148–152. CrossRefGoogle Scholar
  13. 13.
    Abdu Allah HH, El Shorbagi ANA (2016) 5-Aminosalyclic Acid (5-ASA): A Unique Anti-Inflammatory Salicylate. Med Chem (Los Angeles) 6.
  14. 14.
    Abdu-Allah HHM, Abdel-Moty SG, El-Awady R, El-Shorbagi ANA (2016) Design and synthesis of novel 5-aminosalicylate (5-ASA)–4-thiazolinone hybrid derivatives with promising antiproliferative activity. Bioorg Med Chem Lett 26:1647–1650. CrossRefGoogle Scholar
  15. 15.
    Trott O, Olson A (2010) AutoDock Vina: inproving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461. Google Scholar
  16. 16.
    Saleh EM, El-awady RA, Eissa NA, Abdel-Rahman WM (2012) Antagonism between curcumin and the topoisomerase II inhibitor etoposide: A study of DNA damage, cell cycle regulation and death pathways. Cancer Biol Ther 13:1058–1071. CrossRefGoogle Scholar
  17. 17.
    Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV (2014) In vitro cell migration and invasion assays. J Vis Exp 752:e51046. Google Scholar
  18. 18.
    El-Awady RA, Saleh EM, Dahm-Daphi J (2010) Targeting DNA double-strand break repair: Is it the right way for sensitizing cells to 5-fluorouracil? Anti-Cancer Drugs 21:277–287. CrossRefGoogle Scholar
  19. 19.
    He R, Yu Z, Zhang R, Zhang Z (2014) Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin 35:1227–1246. CrossRefGoogle Scholar
  20. 20.
    Prahallad A, Heynen GJJE, Germano G, Willems SM, Evers B, Vecchione L, Gambino V, Lieftink C, Beijersbergen RL, Di Nicolantonio F, Bardelli A, Bernards R (2015) PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs. Cell Rep 12:1978–1985. CrossRefGoogle Scholar
  21. 21.
    Schneeberger VE, Ren Y, Luetteke N, Huang Q, Chen L, Lawrence HR, Lawrence NJ, Haura EB, Koomen JM, Coppola D, Wu J (2015) Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. Oncotarget 6:6191–6202. CrossRefGoogle Scholar
  22. 22.
    Eckert LB, Repasky GA, Ulkü AS, McFall A, Zhou H, Sartor CI, Der CJ (2004) Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res 64:4585–4592. CrossRefGoogle Scholar
  23. 23.
    Perera D, Venkitaraman AR (2016) Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYC-dependent sensitivity to anti-mitotic agents. Sci Rep 6.
  24. 24.
    Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation. Trends Biochem Sci 36:320–328. CrossRefGoogle Scholar
  25. 25.
    Li X, Lu Y, Liang K, Liu B, Fan Z (2005) Differential responses to doxorubicin-induced phosphorylation and activation of Akt in human breast cancer cells. Breast Cancer Res 7:R589–R597. CrossRefGoogle Scholar
  26. 26.
    Li X, Ma H, Li L, Chen Y, Sun X, Dong Z, Liu JY, Zhu W, Zhang JT (2018) Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth. Oncogene.
  27. 27.
    Magi S, Tashiro E, Imoto M (2012) A chemical genomic study identifying diversity in cell migration signaling in cancer cells. Sci Rep 2.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Cijo George Vazhappilly
    • 1
  • Ekram Saleh
    • 1
    • 2
  • Wafaa Ramadan
    • 1
  • Varsha Menon
    • 1
  • Aya Mudhafar Al-Azawi
    • 1
  • Hamadeh Tarazi
    • 1
    • 3
  • Hajjaj Abdu-Allah
    • 4
  • Abdel-Nasser El-Shorbagi
    • 3
    • 4
  • Raafat El-Awady
    • 1
    • 3
    Email author
  1. 1.Sharjah Institute for Medical ResearchUniversity of SharjahSharjahUnited Arab Emirates
  2. 2.Cancer Biology Department, National Cancer InstituteCairo UniversityCairoEgypt
  3. 3.College of PharmacyUniversity of SharjahSharjahUnited Arab Emirates
  4. 4.Medicinal Chemistry Department, College of PharmacyAssuit UniversityAssuitEgypt

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