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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00636

Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells

  • 1Department of Medicine, Solna, Karolinska Institutet, Sweden
  • 2Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden
  • 3Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, Sweden
  • 4Department of Medical Sciences, Clinical Chemistry, Sweden

Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E2 (PGE2) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1β induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE2 production and increased PGF2α and thromboxane B2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways. Moreover, pathway analysis predicted that CIII increased cell death of cancer cells (Z=3.8, p=5.1E-41) while NS-398 decreased the same function (Z=-5.0, p=6.5E-35). In our lipidomics analyses, we found alterations in nine phospholipids between the two inhibitors, with a stronger alteration in the lysophospholipid (LPC) profile with NS-398 compared to CIII. Inhibition of mPGES-1 increased the concentration of sphinganine and dihydroceramide (C16:0DhCer), while inhibition of COX-2 caused a general decrease in most ceramides, again suggesting different effects on cell death between the two inhibitors. We showed that CIII decreased proliferation and potentiated the cytotoxic effect of the cytostatic drugs cisplatin, etoposide, and vincristine when investigated in a live cell imaging system. Our results demonstrate differences in protein and lipid profiles after inhibition of mPGES-1 or COX-2 with important implications on the therapeutic potential of mPGES-1 inhibitors as adjuvant treatment in cancer. We encourage further investigations to illuminate the clinical benefit of mPGES-1 inhibitors in cancer.

Keywords: mPGES-1 inhibitor, PGE2, Cancer, Inflammation, COX-2 inhibitor

Received: 13 Feb 2019; Accepted: 17 May 2019.

Edited by:

Oliver Werz, Friedrich Schiller University Jena, Germany

Reviewed by:

Sabine Grösch, Goethe-Universität Frankfurt am Main, Germany
Ewgenij Proschak, Goethe-Universität Frankfurt am Main, Germany  

Copyright: © 2019 Bergqvist, Ossipova, Idborg, Raouf, Checa, Englund, Englund, Emami Khoonsari, Kultima, Wheelock, Korotkova and Jakobsson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Per-Johan Jakobsson, Department of Medicine, Solna, Karolinska Institutet, Stockholm, 171 76, Stockholm, Sweden, Per-Johan.Jakobsson@ki.se