Targeting Pi3K/Akt/Mtor Pathway Identifies Differential Expression And Functional Role Of Il8 In Liver Cancer Stem Cell Enrichment
| Autor: | Deniz Cansen Kahraman, Rengul Cetin-Atalay, Tamer Kahraman |
|---|---|
| Přispěvatelé: | Kahraman, Tamer |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Sorafenib Cancer Research Carcinoma Hepatocellular Population Antineoplastic Agents 03 medical and health sciences chemistry.chemical_compound Phosphatidylinositol 3-Kinases 0302 clinical medicine Regorafenib Cell Line Tumor medicine Humans Hepatocellular carcinoma (HCC) education Autocrine signalling Protein kinase B neoplasms PI3K/AKT/mTOR pathway Sirolimus education.field_of_study Sulfonamides Stem cell TOR Serine-Threonine Kinases Interleukin-8 Liver Neoplasms medicine.disease digestive system diseases 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Cancer research Neoplastic Stem Cells PI3K/Akt/mTOR Liver cancer Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics |
| Popis: | Activation 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|