Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State

• Published in: Science (American Association for the Advancement of Science) Vol. 341; no. 6143; p. 250
• Main Authors: Santagata, Sandro, Mendillo, Marc L., Tang, Yun-chi, Subramanian, Aravind, Perley, Casey C., Roche, Stéphane P., Wong, Bang, Narayan, Rajiv, Kwon, Hyoungtae, Koeva, Martina, Amon, Angelika, Golub, Todd R., Porco, John A., Whitesell, Luke, Lindquist, Susan
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 19-07-2013; The American Association for the Advancement of Science
• Subjects: Activation; Anabolics; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Benzofurans - pharmacology; Biosynthesis; Cancer; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular metabolism; Chemicals; Culture; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - biosynthesis; Energy Metabolism - drug effects; Gene Expression Regulation, Neoplastic; Genes; Genetics; Heat shock; Heat shock proteins; Heat Shock Transcription Factors; High-Throughput Screening Assays; Humans; Inhibition; Mathematical models; Metabolism; Mice; Neoplasm Transplantation; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Networks; NIH 3T3 Cells; Protein Biosynthesis - drug effects; Protein Biosynthesis - genetics; Protein Biosynthesis - physiology; Protein metabolism; RESEARCH ARTICLE SUMMARY; Ribosomes; Ribosomes - drug effects; Ribosomes - metabolism; Signal transduction; Survival; Transcription Factors - antagonists & inhibitors; Transcription Factors - biosynthesis; Transcriptional regulatory elements; Translation; Translations; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1238303

The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.