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Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively induces death of mTORC1 hyperactive cells.
- Source :
-
Oncotarget [Oncotarget] 2017 Jul 25; Vol. 8 (30), pp. 48711-48724. - Publication Year :
- 2017
-
Abstract
- Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing rapamycin has cytostatic properties rather than a cytotoxic effect. Taking advantage of the enhanced levels of endoplasmic reticulum (ER) stress present in TSC2-null cells, we investigated drug combinations producing a cytotoxic response. We found a nelfinavir and salinomycin combination specifically killed TSC2-deficient, mTORC1 hyperactive cells. Cytotoxicity was rescued by reducing protein synthesis, either through mTORC1 inhibition or cycloheximide treatment. This indicates that the drug combination targets the cells by tipping the protein homeostasis balance of the already metabolically stressed TSC2-deficient cells in favour of cell death. Furthermore, this drug combination also inhibited tumour formation in TSC2-deficient cell models and caused tumour spheroid death in 3D culture. Importantly, the 3D assay could differentiate the cytostatic agent, rapamycin, from the cytotoxic nelfinavir/salinomycin combination. Sporadic cancer cell lines with hyperactive mTORC1 signalling were also susceptible to this nelfinavir/salinomycin drug combination. This work indicates that the protein homeostasis pathway is an attractive therapeutic target in both Tuberous Sclerosis Complex and mTORC1-driven sporadic cancers.
- Subjects :
- Animals
Cell Death drug effects
Drug Therapy, Combination
Endoplasmic Reticulum Stress drug effects
Fibroblasts drug effects
Fibroblasts metabolism
Gene Knockout Techniques
Humans
Mice
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Homeostasis drug effects
Mechanistic Target of Rapamycin Complex 1 metabolism
Nelfinavir pharmacology
Protein Biosynthesis drug effects
Pyrans pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28415776
- Full Text :
- https://doi.org/10.18632/oncotarget.16232