A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture and Reagents
2.2. Treatment of Cells with INR119 and Oxidizing Agents
2.3. Western Blot Analysis
2.4. Quantitative Real-Time PCR (qPCR)
2.5. Statistical Analysis
3. Results
3.1. Phosphorylation of ERK1/2 and p38 under H2O2-Induced Oxidative Stress Is Enhanced by INR119
3.2. Phosphorylation of ERK1/2 and p38 under Phenothiazine-Induced Oxidative Stress Is Enhanced by INR119
3.3. TP53 and BAX Expression under Phenothiazine-Induced Oxidative Stress Is Enhanced by INR119
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Rauch, N.; Rukhlenko, O.S.; Kolch, W.; Kholodenko, B.N. MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance. Curr. Opin. Struct. Biol. 2016, 41, 151–158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Braicu, C.; Buse, M.; Busuioc, C.; Drula, R.; Gulei, D.; Raduly, L.; Rusu, A.; Irimie, A.; Atanasov, A.G.; Slaby, O.; et al. A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers 2019, 11, 1618. [Google Scholar] [CrossRef] [Green Version]
- Tolcher, A.W.; Peng, W.; Calvo, E. Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors. Mol. Cancer Ther. 2018, 17, 3–16. [Google Scholar] [CrossRef] [Green Version]
- Huhn, M.; Engel, R.R.; Leucht, S. Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database Syst. Rev. 2014. [Google Scholar] [CrossRef] [Green Version]
- Hendouei, N.; Saghafi, F.; Shadfar, F.; Hosseinimehr, S.J. Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment. Eur. J. Pharmacol. 2019, 856, 172402. [Google Scholar] [CrossRef]
- Varga, B.; Csonka, Á.; Molnár, J.; Amaral, L.; Spengler, G. Possible Biological and Clinical Applications of Phenothiazines. Anticancer. Res. 2017, 37, 5983–5993. [Google Scholar] [CrossRef] [Green Version]
- Otręba, M.; Kośmider, L.; Rzepecka-Stojko, A. Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review. Eur. J. Pharmacol. 2020, 887, 173553. [Google Scholar] [CrossRef] [PubMed]
- Otręba, M.; Kośmider, L. In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review. J. Appl. Toxicol. 2021, 41, 82–94. [Google Scholar] [CrossRef] [PubMed]
- Antherieu, S.; Azzi, P.B.-E.; Dumont, J.; Fromenty, B.; Robin, M.-A.; Guillouzo, A.; Abdel-Razzak, Z.; Guguen-Guillouzo, C. Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells. Hepatology 2013, 57, 1518–1529. [Google Scholar] [CrossRef]
- Otręba, M.; Beberok, A.; Wrześniok, D.; Rok, J.; Buszman, E. Effect of thioridazine on antioxidant status of HEMn-DP melanocytes. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2015, 388, 1097–1104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, F.; Xia, Y.; Feng, Z.; Lin, W.; Xue, Q.; Jiang, J.; Yu, X.; Peng, C.; Luo, M.; Yang, Y.; et al. Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases. Am. J. Cancer Res. 2019, 9, 459–478. [Google Scholar]
- Otręba, M.; Wrześniok, D.; Beberok, A.; Rok, J.; Buszman, E. Melanogenesis and antioxidant defense system in normal human melanocytes cultured in the presence of chlorpromazine. Toxicol. Vitr. 2015, 29, 221–227. [Google Scholar] [CrossRef]
- Otreba, M.; Wrześniok, D.; Beberok, A.; Rok, J.; Buszman, E. Fluphenazine and perphenazine impact on melanogenesis and antioxidant enzymes activity in normal human melanocytes. Acta Pol. Pharm. Drug Res. 2016, 73, 903–911. [Google Scholar]
- Redwan, I.N.; Dyrager, C.; Solano, C.; De Troconiz, G.F.; Voisin, L.; Bliman, D.; Meloche, S.; Grøtli, M. Towards the development of chromone-based MEK1/2 modulators. Eur. J. Med. Chem. 2014, 85, 127–138. [Google Scholar] [CrossRef] [PubMed]
- Dudley, D.T.; Pang, L.; Decker, S.J.; Bridges, A.J.; Saltiel, A.R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA 1995, 92, 7686–7689. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sjölander, J.J.; Tarczykowska, A.; Picazo, C.; Cossio, I.; Redwan, I.N.; Gao, C.; Solano, C.; Toledano, M.B.; Grøtli, M.; Molin, M.; et al. A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule. Mol. Cell. Biol. 2020, 40, e00346-19. [Google Scholar] [CrossRef] [Green Version]
- Ohren, J.F.; Chen, H.; Pavlovsky, A.; Whitehead, C.; Zhang, E.; Kuffa, P.; Yan, C.; McConnell, P.; Spessard, C.; Banotai, C.; et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 2004, 11, 1192–1197. [Google Scholar] [CrossRef]
- Otręba, M.; Pajor, M.; Warncke, J.D. Antimelanoma activity of perphenazine and prochlorperazine in human COLO829 and C32 cell lines. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2019, 392, 1257–1264. [Google Scholar] [CrossRef] [Green Version]
- Siebel, A.; Cubillos-Rojas, M.; Santos, R.C.; Schneider, T.; Bonan, C.D.; Bartrons, R.; Ventura, F.; De Oliveira, J.R.; Rosa, J.L. Contribution of S6K1/MAPK Signaling Pathways in the Response to Oxidative Stress: Activation of RSK and MSK by Hydrogen Peroxide. PLoS ONE 2013, 8, e75523. [Google Scholar] [CrossRef]
- Barata, A.G.; Dick, T.P. A role for peroxiredoxins in H2O2- and MEKK-dependent activation of the p38 signaling pathway. Redox Biol. 2020, 28, 101340. [Google Scholar] [CrossRef] [PubMed]
- Tang, C.; Liang, J.; Qian, J.; Jin, L.; Du, M.; Li, M.; Li, D. Opposing role of JNK-p38 kinase and ERK1/2 in hydrogen perox-ide-induced oxidative damage of human trophoblast-like JEG-3 cells. Int. J. Clin. Exp. Pathol. 2014, 7, 959–968. [Google Scholar]
- Ruisong, M.; Xiaorong, H.; Gangying, H.; Chunfeng, Y.; Changjiang, Z.; Xuefei, L.; Yuanhong, L.; Hong, J. The Protective Role of Interleukin-33 in Myocardial Ischemia and Reperfusion Is Associated with Decreased HMGB1 Expression and Up-Regulation of the P38 MAPK Signaling Pathway. PLoS ONE 2015, 10, e0143064. [Google Scholar] [CrossRef] [PubMed]
- Song, Y.; Li, X.; Li, Y.; Li, N.; Shi, X.; Ding, H.; Zhang, Y.; Li, X.; Liu, G.; Wang, Z. Non-esterified fatty acids activate the ROS–p38–p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro. Apoptosis 2014, 19, 984–997. [Google Scholar] [CrossRef]
- Gao, M.; Zhao, L.-R. Turning Death to Growth: Hematopoietic Growth Factors Promote Neurite Outgrowth through MEK/ERK/p53 Pathway. Mol. Neurobiol. 2017, 55, 5913–5925. [Google Scholar] [CrossRef] [PubMed]
- Yin, X.; Zhang, R.; Feng, C.; Zhang, J.; Liu, N.; Xu, K.; Wang, X.; Zhang, S.; Li, Z.; Liu, X.; et al. Diallyl disulfide induces G2/M arrest and promotes apoptosis through the p53/p21 and MEK-ERK pathways in human esophageal squamous cell carcinoma. Oncol. Rep. 2014, 32, 1748–1756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Conti, A.; Majorini, M.T.; Elliott, R.; Ashworth, A.; Lord, C.J.; Cancelliere, C.; Bardelli, A.; Seneci, P.; Walczak, H.; Delia, D.; et al. Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway. Oncotarget 2015, 6, 10994–11008. [Google Scholar] [CrossRef] [Green Version]
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Otręba, M.; Sjölander, J.J.; Grøtli, M.; Sunnerhagen, P. A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines. Life 2021, 11, 297. https://doi.org/10.3390/life11040297
Otręba M, Sjölander JJ, Grøtli M, Sunnerhagen P. A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines. Life. 2021; 11(4):297. https://doi.org/10.3390/life11040297
Chicago/Turabian StyleOtręba, Michał, Johanna Johansson Sjölander, Morten Grøtli, and Per Sunnerhagen. 2021. "A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines" Life 11, no. 4: 297. https://doi.org/10.3390/life11040297