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

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 cell...

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Published in:Science (American Association for the Advancement of Science) 2013-07, Vol.341 (6143), p.250-250
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: Article
Language:English
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
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container_title Science (American Association for the Advancement of Science)
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creator 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
description 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.
doi_str_mv 10.1126/science.1238303
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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.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1238303</identifier><identifier>PMID: 23869022</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Activation ; Anabolics ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - isolation &amp; 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 &amp; 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 &amp; inhibitors ; Transcription Factors - biosynthesis ; Transcriptional regulatory elements ; Translation ; Translations ; Tumors</subject><ispartof>Science (American Association for the Advancement of Science), 2013-07, Vol.341 (6143), p.250-250</ispartof><rights>Copyright © 2013 American Association for the Advancement of Science</rights><rights>Copyright © 2013, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-fa5d3fd7ae9f89bb77a44202c5da22b33be52c2f2563f736ef2185dab02f15663</citedby><cites>FETCH-LOGICAL-c487t-fa5d3fd7ae9f89bb77a44202c5da22b33be52c2f2563f736ef2185dab02f15663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23491147$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23491147$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,780,784,2884,2885,27924,27925,58238,58471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23869022$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Santagata, Sandro</creatorcontrib><creatorcontrib>Mendillo, Marc L.</creatorcontrib><creatorcontrib>Tang, Yun-chi</creatorcontrib><creatorcontrib>Subramanian, Aravind</creatorcontrib><creatorcontrib>Perley, Casey C.</creatorcontrib><creatorcontrib>Roche, Stéphane P.</creatorcontrib><creatorcontrib>Wong, Bang</creatorcontrib><creatorcontrib>Narayan, Rajiv</creatorcontrib><creatorcontrib>Kwon, Hyoungtae</creatorcontrib><creatorcontrib>Koeva, Martina</creatorcontrib><creatorcontrib>Amon, Angelika</creatorcontrib><creatorcontrib>Golub, Todd R.</creatorcontrib><creatorcontrib>Porco, John A.</creatorcontrib><creatorcontrib>Whitesell, Luke</creatorcontrib><creatorcontrib>Lindquist, Susan</creatorcontrib><title>Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>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.</description><subject>Activation</subject><subject>Anabolics</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - isolation &amp; purification</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzofurans - pharmacology</subject><subject>Biosynthesis</subject><subject>Cancer</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Neoplastic - drug effects</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Cellular metabolism</subject><subject>Chemicals</subject><subject>Culture</subject><subject>DNA-Binding Proteins - antagonists &amp; 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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
title Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State
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