ArticleCancer biology & therapy2012
Perifosine enhances mTORC1-targeted cancer therapy by activation of GSK3β in NSCLC cells.
Article in Cancer biology & therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Decoding the role of glucocorticoid-regulated kinase 1 in Alzheimer's disease: a promising path toward novel therapeutic strategies.Inflammopharmacology · 2025Review
- Recent advances in non-small cell lung cancer targeted therapy; an update review.Cancer cell international · 2023Review
- Trichostatin A downregulates bromodomain and extra-terminal proteins to suppress osimertinib resistant non-small cell lung carcinoma.Cancer cell international · 2021Article
- p70S6K Promotes Acquired Resistance of Erlotinib Through Induction of Epithelial-Mesenchymal Transition in Non-Small Cell Lung Carcinoma.OncoTargets and therapy · 2020Article
- Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression.Cancer biology & therapy · 2018Article
- Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression.Scientific reports · 2017Article
- p70S6K promotes IL-6-induced epithelial-mesenchymal transition and metastasis of head and neck squamous cell carcinoma.Oncotarget · 2016Article
- Oncogenic miR-9 is a target of erlotinib in NSCLCs.Scientific reports · 2015Article
- SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt.Journal of hematology & oncology · 2013Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
mTORC1 inhibitors, including rapamycin and its analogs, have been actively studied both pre-clinically and clinically. However, the single treatment of mTORC1 inhibitors has been modest in most cancer types. We have previously demonstrated that the activation of PI3K/Akt and MEK/ERK signaling pathways attenuates the anticancer efficacy of mTORC1 inhibitors. In this study, we report that mTORC1 inhibition also phosphorylates and inactivates GSK3β, which is a tumor suppressor in lung cancer. Moreover, we show that perifosine, as an Akt inhibitor, decreases rapamycin-induced phosphorylation of GSK3β and elevated p-GSK3β levels in rapamycin-resistant cell lines. Combination of perifosine with mTORC1 inhibitors showed enhanced anticancer efficacy both in cell cultures and in a xenograft mouse model. In addition, perifosine inhibits the growth of both rapamycin sensitive and resistant A549 cells. However, inhibition of GSK3β by a selective inhibitor- LiCl, or downregulation of GSK3β expression by siRNA, reverses the growth inhibitory effects of perifosine on rapamycin resistant cells, suggesting the important role of GSK3β activation in enhancing mTORC1 inhibitors efficacy by perifosine. Thus, our results provide a potential therapeutic strategy to enhance mTORC1-targeted cancer therapy by using perifosine or targeting GSK3β.
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