System-level responses to cisplatin in pro-apoptotic stages of breast cancer MCF-7 cell line

Cisplatin ceases cell division and induces apoptosis in cancer cell lines. It is well established that cisplatin alters the expression of many genes involved in several cellular processes and pathways including transcription, p53 signaling pathway, and apoptosis. However, system-wide responses to cisplatin in breast cancer cell lines have not been studied. Therefore, we have used a network analysis approach to unveil such responses at early stages of drug treatment. To do this, we have first identified those genes that are responding to cisplatin treatment in MCF-7 cell line. Network and gene ontology analyses were then employed to uncover the molecular pathways affected by cisplatin treatment. Then the results obtained from cisplatin-treated MCF7 cell line were compared to those obtained from other cancer cell lines at comparable time points. In conclusion, we found that ADCY9, GSK3B, MAPK14, NCK1, NCOA2, PIK3CA, PIK3CB, PTK2, RHOB act as hub genes in the cisplatin-responsive regulatory network at the pro-apoptotic stages. The results could be useful in finding new drugs to target these genes in order to obtain similar responses.

[1]  P. Tchounwou,et al.  Cisplatin in cancer therapy: molecular mechanisms of action. , 2014, European journal of pharmacology.

[2]  R. Scott,et al.  Regulators of Global Genome Repair Do Not Respond to DNA Damaging Therapy but Correlate with Survival in Melanoma , 2013, PloS one.

[3]  A. Nebreda,et al.  The Stress Kinase p38α as a Target for Cancer Therapy. , 2015, Cancer research.

[4]  Michael M Gottesman,et al.  Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes , 2012, Pharmacological Reviews.

[5]  Mark Gerstein,et al.  The Importance of Bottlenecks in Protein Networks: Correlation with Gene Essentiality and Expression Dynamics , 2007, PLoS Comput. Biol..

[6]  Ira Mellman,et al.  Endocytosis and cancer. , 2013, Cold Spring Harbor perspectives in biology.

[7]  S. Mello,et al.  Alterations in gene expression profiles correlated with cisplatin cytotoxicity in the glioma U343 cell line , 2010, Genetics and molecular biology.

[8]  J. Gutkind,et al.  G-protein-coupled receptors and cancer , 2007, Nature Reviews Cancer.

[9]  Stefan Wölfl,et al.  Real-Time Monitoring of Cisplatin-Induced Cell Death , 2011, PloS one.

[10]  M. Lacroix-Triki,et al.  RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor , 2013, Breast Cancer Research.

[11]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[12]  S. Pinho,et al.  Glycosylation in cancer: mechanisms and clinical implications , 2015, Nature Reviews Cancer.

[13]  Damian Szklarczyk,et al.  The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible , 2016, Nucleic Acids Res..

[14]  Takeshi Kamiya,et al.  Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment , 2012, International journal of surgical oncology.

[15]  H. Huynh,et al.  MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma , 2015, Molecular Cancer Therapeutics.

[16]  S. B. Prasad,et al.  Sialic acid changes in Dalton's lymphoma-bearing mice after cyclophosphamide and cisplatin treatment. , 2002, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[17]  Hiroyuki Konishi,et al.  The PIK3CA gene is mutated with high frequency in human breast cancers , 2004, Cancer biology & therapy.

[18]  Mathieu Bastian,et al.  Gephi: An Open Source Software for Exploring and Manipulating Networks , 2009, ICWSM.

[19]  S. Al-Bahlani,et al.  Platinum-Based Drugs Differentially Affect the Ultrastructure of Breast Cancer Cell Types , 2017, BioMed research international.

[20]  X. Chen,et al.  The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1. , 2013, Neoplasia.

[21]  Eric Y. Chuang,et al.  Concurrent Gene Signatures for Han Chinese Breast Cancers , 2013, PloS one.

[22]  M. Bader,et al.  Regulation of cell death by the ubiquitin-proteasome system. , 2009, Current opinion in cell biology.

[23]  Andrew J. Wilson,et al.  Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth. , 2015, Cancer letters.

[24]  B. Tsang,et al.  Cisplatin induces p53-dependent FLICE-like inhibitory protein ubiquitination in ovarian cancer cells. , 2008, Cancer research.

[25]  C. Chalfant,et al.  OSU-03012 sensitizes breast cancers to lapatinib-induced cell killing: a role for Nck1 but not Nck2 , 2013, BMC Cancer.

[26]  A. Ridley,et al.  Rho GTPases in cancer cell biology , 2008, FEBS letters.

[27]  Soumya Krishnamurthy,et al.  Cellular Responses to Cisplatin-Induced DNA Damage , 2010, Journal of nucleic acids.

[28]  G. Citro,et al.  Apoptosis Induced by Piroxicam plus Cisplatin Combined Treatment Is Triggered by p21 in Mesothelioma , 2011, PloS one.

[29]  J. Giltnane,et al.  Inhibition of BMP Signaling Suppresses Metastasis in Mammary Cancer , 2014, Oncogene.

[30]  P. Blancafort,et al.  Cisplatin Induces Differentiation of Breast Cancer Cells , 2012, Front. Oncol..

[31]  Shuang Huang,et al.  ATR-Chk2 Signaling in p53 Activation and DNA Damage Response during Cisplatin-induced Apoptosis* , 2008, Journal of Biological Chemistry.

[32]  A. Whale,et al.  Functional characterization of a novel somatic oncogenic mutation of PIK3CB , 2017, Signal Transduction and Targeted Therapy.

[33]  S. Lippard,et al.  Inhibition of transcription by platinum antitumor compounds. , 2009, Metallomics : integrated biometal science.

[34]  G. Kerr,et al.  GSK3β and cyclin D1 expression predicts outcome in early breast cancer patients , 2012, Breast Cancer Research and Treatment.

[35]  Joel Greshock,et al.  High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization , 2005, Breast Cancer Research.

[36]  Hyobin Jeong,et al.  Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation , 2015, PloS one.

[37]  Haiyuan Yu,et al.  Detecting overlapping protein complexes in protein-protein interaction networks , 2012, Nature Methods.

[38]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[39]  H. Iwase.  Molecular action of the estrogen receptor and hormone dependency in breast cancer , 2003, Breast cancer.

[40]  T. Mukohara,et al.  PI3K mutations in breast cancer: prognostic and therapeutic implications , 2015, Breast cancer.

[41]  C. Sorenson,et al.  Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. , 1990, Journal of the National Cancer Institute.

[42]  S. Lippard,et al.  Visualizing inhibition of nucleosome mobility and transcription by cisplatin-DNA interstrand crosslinks in live mammalian cells. , 2013, Cancer research.

[43]  J. Olson,et al.  PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. , 2009, Cancer research.

[44]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.