Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach

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Abstract

The major obstacle in the clinical use of the antitumor drug cisplatin is inherent and acquired resistance. Typically, cisplatin resistance is not restricted to a single mechanism demanding for a systems pharmacology approach to understand a whole cell’s reaction to the drug. In this study, the cellular transcriptome of untreated and cisplatin-treated A549 non-small cell lung cancer cells and their cisplatin-resistant sub-line A549 ^rCDDP ²⁰⁰⁰ was screened with a whole genome array for relevant gene candidates. By combining statistical methods with available gene annotations and without a previously defined hypothesis HRas, MAPK14 (p38) , CCL2, DOK1 and PTK2B were identified as genes possibly relevant for cisplatin resistance. These and related genes were further validated on transcriptome (qRT-PCR) and proteome (Western blot) level to select candidates contributing to resistance. HRas, p38, CCL2, DOK1, PTK2B and JNK3 were integrated into a model of resistance-associated signalling alterations describing differential gene and protein expression between cisplatin-sensitive and -resistant cells in reaction to cisplatin exposure.

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p38 MAP-kinases pathway regulation, function and role in human diseases.

Ana Cuenda, Simon Rousseau (2007)

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.

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Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

Shannon McAuliffe, Stefanie Morgan, Gregory Wyant … (2012)

Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

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The Noncoding RNA Expression Profile and the Effect of lncRNA AK126698 on Cisplatin Resistance in Non-Small-Cell Lung Cancer Cell

Yong Yang, Hui-Hui Li, Shengcai Hou … (2013)

Background The efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer is limited by the acquired drug resistance. Identification the RNAs related to the cisplatin resistance may help to improve clinical response rates. Methods Microarray expression profiling of mRNAs, lncRNA and miRNA was undertaken in A549 cells and cisplatin resistant A549/CDDP cells. Differentially expressed mRNAs, lncRNAs and miRNAs, verified by realtime RT-PCR, were subjected to pathway analysis. Expression of NKD2 and β-catenin was assessed by realtime RT-PCR and western blot analysis. The effect of lncRNA AK126698 on cisplatin induced apoptosis was investigated by annexin-V/PI flow cytometry. Results In total, 1471 mRNAs, 1380 lncRNAs and 25 miRNAs differentially expressed in A549/CDDP and A549 cells. Among them, 8 mRNAs, 8 lncRNAs and 5 miRNAs differentially expressed in gene chip analysis were validated. High-enrichment pathway analysis identified that some classical pathways participated in proliferation, differentiation, avoidance of apoptosis, and drug metabolism were differently expressed in these cells lines. Gene co-expression network identified many genes like FN1, CTSB, EGFR, and NKD2; lncRNAs including BX648420, ENST00000366408, and AK126698; and miRNAs such as miR-26a and let-7i potentially played a key role in cisplatin resistance. Among which, the canonical Wnt pathway was investigated because it was demonstrated to be targeted by both lncRNAs and miRNAs including lncRNA AK126698. Knockdown lncRNA AK126698 not only greatly decreased NKD2 which can negatively regulate Wnt/β-catenin signaling but also increased the accumulation and nuclear translocation of β-catenin, and significantly depressed apoptosis rate induced by cisplatin in A549 cells. Conclusion Cisplatin resistance in non-small-cell lung cancer cells may relate to the changes in noncoding RNAs. Among these, AK126698 appears to confer cisplatin resistance by targeting the Wnt pathway.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 07 March 2018

Publication date Collection: March 2018

Volume: 19

Issue: 3

Electronic Location Identifier: 767

Affiliations

[1 ]Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121 Bonn, Germany; n.sarin@ 123456uni-bonn.de

[2 ]Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany; engel_florian@ 123456hotmail.de (F.E.); Roland.Froetschl@ 123456bfarm.de (R.F.)

[3 ]Institute of Medical Virology, Goethe University Hospital Frankfurt, 60596 Frankfurt/Main, Germany; f.rothweiler@ 123456kinderkrebsstiftung-frankfurt.de (F.R.); cinatl@ 123456em.uni-frankfurt.de (J.C.J.)

[4 ]Industrial Biotechnology Centre and School of Biosciences, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK; M.Michaelis@ 123456kent.ac.uk

[5 ]Bonn-Aachen International Center for IT (b-it), Life Science Data Analytics & Algorithmic Bioinformatics, University of Bonn, 53115 Bonn, Germany; frohlich@ 123456bit.uni-bonn.de

Author notes

[* ]Correspondence: akalayda@ 123456uni-bonn.de ; Tel.: +49-228-73-5256

[†]

These authors contributed equally to this work.

Author information

Roland Frötschl https://orcid.org/0000-0001-8721-7509

Holger Fröhlich https://orcid.org/0000-0002-5328-1243

Ganna V. Kalayda https://orcid.org/0000-0002-7196-8137

Article

Publisher ID: ijms-19-00767

DOI: 10.3390/ijms19030767

PMC ID: 5877628

PubMed ID: 29518977

SO-VID: 0aa63c0a-b774-4d43-8bb4-510e5022c4af

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach

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Higher order chromatin architecture

Most cited references 47

p38 MAP-kinases pathway regulation, function and role in human diseases.

Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

The Noncoding RNA Expression Profile and the Effect of lncRNA AK126698 on Cisplatin Resistance in Non-Small-Cell Lung Cancer Cell

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