Genome-wide shRNA screen reveals increased mitochondrial dependence upon mTORC2 addiction

Release from growth factor dependence and acquisition of signalling pathway addiction are critical steps in oncogenesis. To identify genes required on mammalian target of rapamycin (mTOR) addiction, we performed a genome-wide short hairpin RNA screen on a v-H-ras-transformed Pten-deficient cell line...

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Bibliographic Details
Published in:	Oncogene Vol. 30; no. 13; pp. 1551 - 1565
Main Authors:	Colombi, M, Molle, K D, Benjamin, D, Rattenbacher-Kiser, K, Schaefer, C, Betz, C, Thiemeyer, A, Regenass, U, Hall, M N, Moroni, C
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 31-03-2011 Nature Publishing Group
Subjects:	631/443/319/333 631/67 631/80/83/2359 Addictions Adenosine Triphosphate - biosynthesis Animals Apoptosis ATP Biological and medical sciences Cell Biology Cell Line, Tumor Cell physiology Cell Proliferation Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular biology Cellular signal transduction Electron transport Fibroblasts Fundamental and applied biological sciences. Psychology Genetic aspects Genetic screening Genomes Genomics Glucose - metabolism H-Ras protein Human Genetics Humans Interleukin 3 Interleukin-3 - pharmacology Internal Medicine Medicine Medicine & Public Health Mice Mitochondria Mitochondria - physiology Mitochondrial DNA Molecular and cellular biology Oncology original-article Pharmacology Physiological aspects PTEN protein Rapamycin RNA RNA Interference RNA, Small Interfering - genetics Signal Transduction siRNA Therapeutic targets TOR protein TOR Serine-Threonine Kinases - physiology Trans-Activators - physiology Tumor cell lines Tumorigenesis Switzerland drug targets shRNA screen IL-3 dependence mitochondria mTOR addiction Mitochondria Addiction Interleukin 3 Cytokine Short hairpin RNA Carcinogenesis
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Summary:	Release from growth factor dependence and acquisition of signalling pathway addiction are critical steps in oncogenesis. To identify genes required on mammalian target of rapamycin (mTOR) addiction, we performed a genome-wide short hairpin RNA screen on a v-H-ras-transformed Pten-deficient cell line that displayed two alternative growth modes, interleukin (IL)-3-independent/mTOR-addicted proliferation (transformed growth mode) and IL-3-dependent/mTOR-non-addicted proliferation (normal growth mode). We screened for genes required only in the absence of IL-3 and thus specifically for the transformed growth mode. The top 800 hits from this conditional lethal screen were analyzed in silico and 235 hits were subsequently rescreened in two additional Pten-deficient cell lines to generate a core set of 47 genes. Hits included genes encoding mTOR and the mTOR complex 2 (mTORC2) component rictor and several genes encoding mitochondrial functions including components of the respiratory chain, adenosine triphosphate synthase, the mitochondrial ribosome and mitochondrial fission factor. Small interfering RNA knockdown against a sizeable fraction of these genes triggered apoptosis in human cancer cell lines but not in normal fibroblasts. We conclude that mTORC2-addicted cells require mitochondrial functions that may be novel drug targets in human cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2010.539