ArticleMolecular cancer therapeutics2015
Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 56 citations in OpenAlex.
- Targeting mTOR with vistusertib attenuates metabolic steatohepatitis and prevents HCC development.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Viral-host interactions mediated by the mTOR signaling pathway.Cell insight · 2026Review
- A cancer neuroscience-related gene model for prognosis prediction and immunotherapy response evaluation in breast cancer.Discover oncology · 2026Article
- Article
- Prognostic signature and immune efficacy of mJournal of Cancer · 2024Article
- Genomic gain/methylation modification/hsa-miR-132-3p increases RRS1 overexpression in liver hepatocellular carcinoma.Cancer science · 2023Article
- Therapeutic avenues for targeting treatment challenges of diffuse midline gliomas.Neoplasia (New York, N.Y.) · 2023Review
- Construction of a miRNA-mRNA network related to exosomes in metastatic hepatocellular carcinoma.Heliyon · 2023Article
- Role of mammalian target of rapamycin complex 2 in primary and secondary liver cancer.World journal of gastrointestinal oncology · 2021Review
- LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3.Journal of experimental & clinical cancer research : CR · 2021Article
- Regulation of ABC Drug Efflux Transporters in Human T-Cells Exposed to an HIV Pseudotype.Frontiers in pharmacology · 2021Article
- Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma.International journal of molecular sciences · 2020Article
- Epithelial-to-mesenchymal transition markers are differentially expressed in epithelial cancer cell lines after everolimus treatment.Oncology letters · 2020Article
- gga-microRNA-375 negatively regulates the cell cycle and proliferation by targeting Yes-associated protein 1 in DF-1 cells.Experimental and therapeutic medicine · 2020Article
- Mammalian Target of Rapamycin Complex 2 Signaling Is Required for Liver Regeneration in a Cholestatic Liver Injury Murine Model.The American journal of pathology · 2020Article
- Shisa3 brakes resistance to EGFR-TKIs in lung adenocarcinoma by suppressing cancer stem cell properties.Journal of experimental & clinical cancer research : CR · 2019Article
- Combined mTORC1/mTORC2 inhibition blocks growth and induces catastrophic macropinocytosis in cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The mTORC2-Akt1 Cascade Is Crucial for c-Myc to Promote Hepatocarcinogenesis in Mice and Humans.Hepatology (Baltimore, Md.) · 2019Article
- Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson's Disease.International journal of molecular sciences · 2019Review
- Doxorubicin induces an extensive transcriptional and metabolic rewiring in yeast cells.Scientific reports · 2018Article
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0-G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027-induced cell-cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. Mol Cancer Ther; 14(8); 1805-15. ©2015 AACR.
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