Valproic acid inhibits the protective effects of stromal cells against chemotherapy in breast cancer: Insights from proteomics and systems biology

• Published in: Journal of cellular biochemistry Vol. 119; no. 11; pp. 9270 - 9283
• Main Authors: Barneh, Farnaz, Salimi, Mona, Goshadrou, Fatemeh, Ashtiani, Minoo, Mirzaie, Mehdi, Zali, Hakimeh, Jafari, Mohieddin
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-11-2018
• Subjects: AKT protein; Anticancer properties; Antioxidants; Bone marrow; Breast cancer; Cancer; Cell activation; Cellular communication; Chemoresistance; Chemotherapy; Cytokines; drug resistance; Gene expression; Growth factors; Janus kinase; Kinases; Lymphocytes B; Mesenchyme; Oxidative stress; Proteins; Proteomics; Secretome; Stem cells; Stromal cells; systems biology; Transcription activation; Transforming growth factor-b; Tumor cells; tumor microenvironment; Tumors; Valproic acid; systems biology; cancer; drug resistance; tumor microenvironment; valproic acid; proteomics
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27196

Interaction between tumor and stromal cells is beginning to be decoded as a contributor to chemotherapy resistance. Here, we aim to take a system‐level approach to explore a mechanism by which stromal cells induce chemoresistance in cancer cells and subsequently identify a drug that can inhibit such interaction. Using a proteomic dataset containing quantitative data on secretome of stromal cells, we performed multivariate analyses and found that bone‐marrow mesenchymal stem cells (BM‐MSCs) play the most protective role against chemotherapeutics. Pathway enrichment tests showed that secreted cytokines from BM‐MSCs activated 4 signaling pathways including Janus kinase‐signal transducer and activator of transcription, phosphatidylinositol 3‐kinase‐protein kinase B, and mitogen‐activated protein kinase, transforming growth factor‐β in cancer cells collectively leading to nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐kB) transcription factor activation. Based on the data from integrated Library of Integrated Network‐Based Cellular Signatures (iLINCs) program, we found that among different drugs, valproic acid (VA) affected the expression of 34 genes within the identified pathways that are activated by stromal cells. Our in vitro experiments confirmed that VA inhibits NF‐kB activation in cancer cells. In addition, analyzing gene expression data in patients taking oral VA showed that this drug decreased expression of antioxidant enzymes culminating in increased oxidative stress in tumor cells. These results suggest that VA confines the protective role of stromal cells by inhibiting the adaptation mechanisms toward oxidative stress which is potentiated by stromal cells. Since VA is an already prescribed drug manifesting anticancer effects, this study provides a mechanistic insight for combination of VA with chemotherapy in the clinical setting.
Stromal cells within breast tumor microenvironment secrete myriads of factors that collectively converge on nuclear factor kappa‐light‐chain‐enhancer of activated B cells transcription factor and protect cancer cells from chemotherapy‐induced cytotoxicity. Based on genome‐wide drug signatures, we found that valproic acid, an histone deacetylase inhibitor, was an effective drug to inhibit stromal cell protection.