Open Access

Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells

  • Authors:
    • Nimmi A. Thomas
    • Rita G. Abraham
    • Brixhilda Dedi
    • Nancy A. Krucher
  • View Affiliations

  • Published online on: December 7, 2018     https://doi.org/10.3892/ijo.2018.4658
  • Pages: 527-536
  • Copyright: © Thomas et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a particularly lethal disease that is resistant to targeted therapies. Tyrosine kinase inhibitors (TKIs), including erlotinib and gefitinib, which block the action of the human epidermal growth factor receptor type 1 receptor, provide small increases in patient survival when administered with gemcitabine. The retinoblastoma (Rb) tumor suppressor protein is an additional target in pancreatic cancer, due to its documented inactivation in PDAC. The present study, using cell number, apoptosis and immunoblotting assays, aimed to evaluate the effects of activation of the Rb tumor suppressor via dephosphorylation by small interfering RNA‑mediated phosphatase activation. In the Panc1, MIAPaCa‑2 and Capan‑2 pancreatic cancer cell lines, and in normal H6c7 cells, the effects of phosphatase activation on Rb were revealed to be dependent on expression of the p16 tumor suppressor, which regulates Rb phosphorylation. Phosphatase activation had no effect on non‑transformed pancreatic epithelial cells. When comparing kinase inhibition with phosphatase activation, it was demonstrated that kinase inhibition reduced proliferation, whereas phosphatase activation induced apoptosis. Both treatments together resulted in a greater reduction of pancreatic cancer cells than either treatment alone. In addition, the effects of combination treatment of phosphatase activation with TKIs on cell number and activation of the signal transducer and activator of transcription 3 (STAT3) resistance pathway were determined. The combination of Rb phosphatase activation with TKIs resulted in a greater reduction in cell number compared with either treatment alone, without STAT3 pathway activation. These data suggested that targeting Rb phosphorylation by activating phosphatase may be a rational strategy to inhibit pancreatic tumor cell growth, without activation of acquired resistance.
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February-2019
Volume 54 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Thomas NA, Abraham RG, Dedi B and Krucher NA: Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. Int J Oncol 54: 527-536, 2019
APA
Thomas, N.A., Abraham, R.G., Dedi, B., & Krucher, N.A. (2019). Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. International Journal of Oncology, 54, 527-536. https://doi.org/10.3892/ijo.2018.4658
MLA
Thomas, N. A., Abraham, R. G., Dedi, B., Krucher, N. A."Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells". International Journal of Oncology 54.2 (2019): 527-536.
Chicago
Thomas, N. A., Abraham, R. G., Dedi, B., Krucher, N. A."Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells". International Journal of Oncology 54, no. 2 (2019): 527-536. https://doi.org/10.3892/ijo.2018.4658