ArticleMolecular oncology2015
Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- TSC2 is a stress granule suppressor.bioRxiv : the preprint server for biology · 2026Article
- New insights into tuberous sclerosis complex: from structure to pathogenesis.Frontiers in cell and developmental biology · 2025Review
- Antiretroviral Drugs Impact Autophagy: Opportunities for Drug Repurposing.Frontiers in bioscience (Landmark edition) · 2024Review
- Nelfinavir inhibition of Kaposi's sarcoma-associated herpesvirus protein expression and capsid assembly.Infectious agents and cancer · 2024Article
- Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy.International journal of nanomedicine · 2024Review
- Repurposing approved non-oncology drugs for cancer therapy: a comprehensive review of mechanisms, efficacy, and clinical prospects.European journal of medical research · 2023Review
- Differential ER stress as a driver of cell fate following ricin toxin exposure.FASEB bioAdvances · 2022Article
- Long-Term Effects of Sirolimus on Human Skin TSC2-Null Fibroblast‒Like Cells.The Journal of investigative dermatology · 2021Article
- Review
- The paradox of autophagy in Tuberous Sclerosis Complex.Genetics and molecular biology · 2021Article
- Review
- Tuberous sclerosis: a review of the past, present, and futureTurkish journal of medical sciences · 2020Review
- Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer.Journal of experimental & clinical cancer research : CR · 2018Article
- Article
- Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment.Cancers · 2018Article
- Autophagy inhibitor chloroquine induces apoptosis of cholangiocarcinoma cells via endoplasmic reticulum stress.Oncology letters · 2018Article
- Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively induces death of mTORC1 hyperactive cells.Oncotarget · 2017Article
- The HIV protease and PI3K/Akt inhibitor nelfinavir does not improve the curative effect of fractionated irradiation in PC-3 prostate cancerClinical and translational radiation oncology · 2017Article
- Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex.Cancer science · 2017Review
- The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia.OncoTargets and therapy · 2017Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug-induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.