Targeting PI3K/AKT/mTOR pathway identifies differential expression and functional role of IL8 in liver cancer stem cell enrichment

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buir.contributor.authorKahraman, Tamer
dc.citation.epage2157en_US
dc.citation.issueNumber11en_US
dc.citation.spage2146en_US
dc.citation.volumeNumber18en_US
dc.contributor.authorKahraman, D. C.en_US
dc.contributor.authorKahraman, Tameren_US
dc.contributor.authorÇetin-Atalay, R.en_US
dc.date.accessioned2020-02-13T11:33:54Z
dc.date.available2020-02-13T11:33:54Z
dc.date.issued2019
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractActivation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out IL8 expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.en_US
dc.identifier.doi10.1158/1535-7163.MCT-19-0004en_US
dc.identifier.issn1535-7163
dc.identifier.urihttp://hdl.handle.net/11693/53336
dc.language.isoEnglishen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.relation.isversionofhttps://dx.doi.org/10.1158/1535-7163.MCT-19-0004en_US
dc.source.titleMolecular Cancer Therapeuticsen_US
dc.subjectLiver canceren_US
dc.subjectStem cellen_US
dc.subjectPI3K/Akt/mTORen_US
dc.subjectHepatocellular carcinoma (HCC)en_US
dc.titleTargeting PI3K/AKT/mTOR pathway identifies differential expression and functional role of IL8 in liver cancer stem cell enrichmenten_US
dc.typeArticleen_US
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