Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis

Storm, P., Aits, S., Puthia, M. K., Urbano, A., Northen, T., Powers, S., Bowen, B., Chao, Y., Reindl, W., Lee, D. Y., Sullivan, N. L., Zhang, J., Trulsson, M., Yang, H., Watson, J. D., Svanborg, C. (June 2011) Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis. Oncogene, 30 (48). pp. 4765-4779. ISSN 09509232 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21643007
DOI: 10.1038/onc.2011.196

Abstract

HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1α modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing ∼8000 targets, and HK activity decreased within 15 min of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 min. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Microarray Service
CSHL labs
CSHL labs > Powers lab
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: Matt Covey
Date: 6 June 2011
Date Deposited: 05 Feb 2013 22:08
Last Modified: 30 Oct 2015 20:44
PMCID: PMC4041205
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27190

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