Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy

Our plain-English summary of Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy, by S. Borchert, P.M. Suckrau, M. Wessolly, et al (Journal of Oncology, 2019).

The study

• Authors: S. Borchert, P.M. Suckrau, M. Wessolly, E. Mairinger, B. Hegedus, T. Hager, T. Herold, W.E.E. Eberhardt, J. Wohlschlaeger, C. Aigner, A. Bankfalvi, K.W. Schmid, R.F.H. Walter, F.D. Mairinger
• Journal: Journal of Oncology
• Published: 2019;2019:2902985
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumor associated with a dismal prognosis. Multimodal therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons underlying the rather poor efficacy of platinum compounds remain largely unknown. Kinase activity might influence cellular response to these regimens.

Materials And Methods: For this exploratory study, we screened MPM cell lines (NCI-H2452, NCI-H2052, and MSTO-211H) differing in response to cisplatin and benign control fibroblasts (MRC-5) for overall phosphorylation patterns as well as kinase activity with respect to cellular response to cisplatin-based therapeutics. We analysed the cell lines for cellular kinases in a high-throughput manner using the highly innovative technique PamGene. Cell state analysis including apoptosis, necrosis, and cell viability was performed by using enzyme activity and fluorescent-based assays.

Results: Cisplatin alters cellular phosphorylation patterns affecting cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis. In cisplatin-responsive cell lines, phosphorylation of AKT1 and GSK3B was decreased but could not be influenced in cisplatin-resistant NCI-H2452 cells. Cisplatin-responsive cell lines showed increased phosphorylation levels of JNK1/2/3 but decreased phosphorylation in cisplatin-resistant NCI-H2452 cells.

Conclusion: Kinase phosphorylation and activity might play a crucial role in cellular response to cytostatic agents. Cisplatin influences phosphorylation patterns with distinct features in cisplatin-resistant cells. These alterations exert a significant impact on cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis of the respective tumor cells. Based on our results, the induction of p38 or JNK1/3, or inhibition of AKT1 by, for example, BIA-6, might offer a positive synergistic effect by induction of an apoptotic response to cisplatin-based treatment, thus potentially enhancing the clinical outcome of MPM patients.

Copyright © 2019 Sabrina Borchert et al.

In plain English

This was a laboratory study of cancer cells grown in dishes. It did not study patients or asbestos exposure. The authors used three malignant pleural mesothelioma cell lines that respond differently to the chemotherapy drug cisplatin: NCI-H2052 (sensitive), MSTO-211H (moderately sensitive) and NCI-H2452 (resistant). A human lung-fibroblast cell line, MRC-5, served as a control. The cells were treated with 10 μM cisplatin for 48 hours. The authors then measured protein phosphorylation (chemical tagging) and estimated the activity of enzymes called kinases. The results section reported 54 protein sites with significantly altered phosphorylation during cisplatin treatment (a figure caption gives 77), with an overall reduction at tyrosine sites. High phosphorylation of ESR1, LAT, PTN12 and PTN6 was most strongly linked to less apoptosis, a form of cell death, after cisplatin; the authors called this an apoptosis-preventing effect. NCI-H2052 cells showed the strongest changes in AKT1 phosphorylation, while the resistant NCI-H2452 cells showed no significant change. The authors concluded that blocking AKT1 (for example with BIA-6), or activating p38 or JNK1/3, might work together with cisplatin to promote cell death.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Exploratory laboratory study of cultured cell lines (in vitro)
• Who was studied: Three malignant pleural mesothelioma (MPM) cell lines: MSTO-211H (biphasic subtype, moderately cisplatin sensitive), NCI-H2052 (epithelioid subtype, cisplatin sensitive) and NCI-H2452 (sarcomatoid subtype, cisplatin-resistant). The human lung-fibroblast cell line MRC-5 was the control. No patients were studied.
• Exposure: The chemotherapy drug cisplatin at 10 μM for 48 hours, compared with untreated cells in medium. Asbestos exposure was not studied.
• Main results:
  • The results section reports that 54 phosphosites showed significantly altered phosphorylation during cisplatin treatment across the cell lines. The Figure 2 caption gives 77 instead.
  • Two phosphosites (PPR1A and FOXO3) showed increased phosphorylation with cisplatin.
  • There was a significant overall reduction in phosphorylation of tyrosine phosphosites with cisplatin.
  • Phosphorylation levels of 24 phosphosites were related to the cells' apoptosis after cisplatin. High phosphorylation of ESR1, LAT, PTN12 and PTN6 was most strongly linked to less apoptosis, which the authors called the strongest apoptosis-preventing effect.
  • NCI-H2052 cells showed the strongest changes in AKT1 phosphorylation during cisplatin treatment.
  • In cisplatin-resistant NCI-H2452 cells, AKT1 phosphorylation did not differ significantly between treated and untreated cells.
  • In NCI-H2052 cells, cisplatin led to a 2.5 to 3-fold decrease in the estimated kinase activity of FGFR1, FES and ALK.
  • In NCI-H2052 and in MRC-5 control cells, the estimated kinase activity of ERK1/2 and CDK1 increased 2.3-fold with cisplatin.
  • The authors reported elevated JNK1/2/3 activity in NCI-H2052 and MRC-5 cells, and decreased JNK1/3 phosphorylation in cisplatin-resistant NCI-H2452 cells.
  • For BTLA, the authors could not detect cellular effects of the differences in phosphorylation in their cell state analysis.
• The authors' conclusion: The authors concluded that inhibiting AKT1 (for example with BIA-6), or inducing p38 or JNK1/3, might work together with cisplatin by inducing cell death. They wrote that this could potentially improve patients' clinical outcome.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Prognosis, Multimodal Therapy, Cisplatin, Fibroblast, Apoptosis, Necrosis.

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