Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs
2015 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, E51-E61 p.Article in journal (Refereed) Published
The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon-(IFN)-stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock-down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor-9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors. What's new? Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.
Place, publisher, year, edition, pages
2015. Vol. 136, no 4, E51-E61 p.
multicellular spheroids, IRF9, interferon-stimulated genes, STAT transcription factors, chemoresistance
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-241382DOI: 10.1002/ijc.29161ISI: 000346089900005PubMedID: 25156627OAI: oai:DiVA.org:uu-241382DiVA: diva2:783535