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Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells.
Front Pharmacol. 2019; 10:636.FP

Abstract

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 PGF 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.

Authors+Show Affiliations

Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.Department of Analytical Chemistry, Stockholm University, Stockholm, Sweden.Department of Analytical Chemistry, Stockholm University, Stockholm, Sweden.Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31231223

Citation

Bergqvist, Filip, et al. "Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells." Frontiers in Pharmacology, vol. 10, 2019, p. 636.
Bergqvist F, Ossipova E, Idborg H, et al. Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells. Front Pharmacol. 2019;10:636.
Bergqvist, F., Ossipova, E., Idborg, H., Raouf, J., Checa, A., Englund, K., Englund, P., Khoonsari, P. E., Kultima, K., Wheelock, C. E., Larsson, K., Korotkova, M., & Jakobsson, P. J. (2019). Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells. Frontiers in Pharmacology, 10, 636. https://doi.org/10.3389/fphar.2019.00636
Bergqvist F, et al. Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells. Front Pharmacol. 2019;10:636. PubMed PMID: 31231223.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells. AU - Bergqvist,Filip, AU - Ossipova,Elena, AU - Idborg,Helena, AU - Raouf,Joan, AU - Checa,Antonio, AU - Englund,Karin, AU - Englund,Petter, AU - Khoonsari,Payam Emami, AU - Kultima,Kim, AU - Wheelock,Craig E, AU - Larsson,Karin, AU - Korotkova,Marina, AU - Jakobsson,Per-Johan, Y1 - 2019/06/07/ PY - 2019/02/13/received PY - 2019/05/17/accepted PY - 2019/6/25/entrez PY - 2019/6/25/pubmed PY - 2019/6/25/medline KW - cancer KW - cyclooxygenase-2 inhibitor KW - inflammation KW - microsomal prostaglandin E synthase-1 inhibitor KW - prostaglandin E2 SP - 636 EP - 636 JF - Frontiers in pharmacology JO - Front Pharmacol VL - 10 N2 - 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. SN - 1663-9812 UR - https://www.unboundmedicine.com/medline/citation/31231223/Inhibition_of_mPGES_1_or_COX_2_Results_in_Different_Proteomic_and_Lipidomic_Profiles_in_A549_Lung_Cancer_Cells_ L2 - https://doi.org/10.3389/fphar.2019.00636 DB - PRIME DP - Unbound Medicine ER -
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