Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Thwarting Protein Production Slows Cancer Cells’ Malignant March

Published: Tuesday, July 23, 2013
Last Updated: Tuesday, July 23, 2013
Bookmark and Share
Protein production or translation is tightly coupled to a highly conserved stress response that cancer cells rely on for survival and proliferation.

In mouse models of cancer, targeted therapeutic inhibition of translation disrupts this survival response, dramatically slowing tumor growth and potentially rendering drug-resistant tumors vulnerable to other therapies.

From yeast to worms to humans, this stress response and its primary regulator, heat shock factor 1 (HSF1), help normal cells adapt to harsh environments, including the presence of heavy metals, high salt concentrations, low oxygen levels, and of course increased temperatures.

"In a perverted twist of fate, cancer cells take advantage of this incredibly ancient survival strategy—the heat shock response—to help them survive despite the best efforts of our own natural defenses, and sophisticated therapeutics, to kill them,” says Whitehead Member Susan Lindquist. “And trumping all that, we find it not only helps them survive, it helps them thrive!"

Across tumor and cancer types, cancer cells rely on the heat shock response and HSF1 to support the production of vast quantities of proteins and the high-energy demands needed to propel malignancy. Accordingly, researchers have envisioned HSF1 as a potential therapeutic target, but such transcriptional regulators have been notoriously difficult to target. However, by determining that protein translation is intimately connected to HSF1 activity, Whitehead scientists may have identified an approach to controlling cancer cells’ overactive heat shock response. Their work is described in this week’s issue of the journal Science.

“The genetic screens that we conducted in collaboration with the Broad Institute and the drug screens that were conducted by Sandro Santagata (Lindquist lab postdoctoral researcher) all pointed to this connection—that the process of protein production signals to HSF1,” says Marc Mendillo, a postdoctoral researcher in Lindquist’s lab and a coauthor of the Science paper with Santagata. “And this link may explain the HSF1 activation we have observed across an extraordinarily broad range of human cancers.”

Santagata’s screens identified one compound that was particularly effective at disrupting translation and HSF1 activity. Collaborators at Boston University synthesized an analog of this compound, called Rohinitib (RHT), that is even more efficacious. Normal cells are relatively resistant to RHT and seem to be little affected by it. However, cells from a wide spectrum of cancers are sensitive to it—RHT added to cancer cells in vitro normalizes their metabolism, including the increased glucose uptake characteristic of such cells, and even kills them. Blood cancer lines are highly sensitive to RHT and show the most dramatic effects. In mice implanted with human myeloid leukemia tumors, RHT greatly inhibited the tumors’ growth and suppressed glucose uptake, similar to the effects seen in vitro.

“I think we’ve found a very simple but elegant biological principle here, which makes sense,” says Santagata. “Systems in the cell that need to work together—such as protein translation and the heat shock response—actually are linked together. We found that link using small molecules, which means that we now have the tools in hand to suppress what cancer has coopted. We can use those chemicals to thwart the cancer cells’ ability to harness the properties of HSF1.

Such chemicals may be enough to knock cancer cells off balance, but the final coup de grace may need to come from other therapeutics.

“You probably want to have these kinds of effects in the context of other therapeutic interventions,” says Luke Whitesell, an oncologist and senior research scientist in the Lindquist lab. “If you were to compromise the altered physiology of tumors with something like RHT, the cancer cells are going to be less able to tolerate other therapeutic insults, and that probably would give you more effective therapies. But we don’t know what the best combinations are going to be yet.”


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Super-Enhancers Seen as ‘Rosetta Stone’ for Dialog Between Genes and Disease
Regulatorsthat control cell identity found to be enriched in mutated regions of genome.
Monday, October 21, 2013
Sex Chromosome Shocker: The “Female” X a Key Contributor to Sperm Production
Painstaking new analysis of the genetic sequence of the X chromosome reveals that large portions of the X have evolved to play a specialized role in sperm production.
Tuesday, July 23, 2013
Scientists Identify Gene that Controls Aggressiveness in Breast Cancer Cells
Researchers have identified a transcription factor, known as ZEB1, that is capable of converting non-aggressive basal-type cancer cells into highly malignant, tumor-forming cancer stem cells (CSCs).
Monday, July 08, 2013
Precision Gene Targeting in Stem Cells Corrects Disease-Causing Mutations
Whitehead Institute researchers manipulate targeted genes in both human embryonic stem cells and induced pluripotent stem cells.
Tuesday, July 19, 2011
Embryonic Stem Cells Reveal Oncogene's Secret Growth Formula
Researchers describes a pausing step in the transcription process that serves to regulate expression of as many as 80% of the genes in mammalian cells.
Monday, May 03, 2010
Chimp and Human Y Chromosomes Evolving Faster than Expected
Whitehead Institute researchers have found considerable differences in the genetic sequences of the human and chimpanzee Y Chromosomes.
Wednesday, January 20, 2010
Knockouts in Human Cells Point to Pathogenic Targets
Whitehead researchers have developed a new type of genetic screen for human cells to pinpoint specific genes and proteins used by pathogens.
Monday, November 30, 2009
Technique Enables Efficient Gene Targeting In Human Embryonic Stem Cells
Whitehead scientists have developed a technique to modify or introduce genes into the genomes of human ESCs and iPS cells.
Thursday, August 27, 2009
Novel Cell Lines Propel the Search for Safer Stem Cell Induction
Researchers produce mice and mouse cell lines with identical configurations of the specific factors needed to reprogram adult cells to an embryonic-stem-cell-like state.
Thursday, January 22, 2009
Single Virus Used to Convert Adult Cells to Embryonic Stem Cell-Like Cells
Researchers have simplified the creation of induced pluripotent stem cells, cutting the number of viruses used in the reprogramming process from four to one.
Monday, December 22, 2008
Recipe for Cell Reprogramming Adds Protein
A drug-like molecule can be substituted for the cancer gene c-Myc, one of four genes added to adult cells to reprogram them to an embryonic-stem-cell-like state, says Whitehead researchers.
Friday, August 08, 2008
Scientists Identify Gene that Regulates Polarity in Regenerating Flatworms
Whitehead scientists have discovered that the gene Smed-beta-catenin-1 is required for proper decisions about head-versus-tail polarity in regenerating flatworms.
Monday, December 10, 2007
Scientific News
Poor Survival Rates in Leukemia Linked to Persistent Genetic Mutations
For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.
Searching Big Data Faster
Theoretical analysis could expand applications of accelerated searching in biology, other fields.
Growing Hepatitis C in the Lab
Recent discovery allows study of naturally occurring forms of hepatitis C virus (HCV) in the lab.
Inciting an Immune Attack on Cancer Cells
A new minimally invasive vaccine that combines cancer cells and immune-enhancing factors could be used clinically to launch a destructive attack on tumors.
Reprogramming Cancer Cells
Researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.
Genetic Overlapping in Multiple Autoimmune Diseases May Suggest Common Therapies
CHOP genomics expert leads analysis of genetic architecture, with eye on repurposing existing drugs.
Surprising Mechanism Behind Antibiotic-Resistant Bacteria Uncovered
Now, scientists at TSRI have discovered that the important human pathogen Staphylococcus aureus, develops resistance to this drug by “switching on” a previously uncharacterized set of genes.
How DNA ‘Proofreader’ Proteins Pick and Edit Their Reading Material
Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have discovered how two important proofreader proteins know where to look for errors during DNA replication and how they work together to signal the body’s repair mechanism.
Fat in the Family?
Study could lead to therapeutics that boost metabolism.
Tissue Bank Pays Dividends for Brain Cancer Research
Checking what’s in the bank – the Brisbane Breast Bank, that is – has paid dividends for UQ cancer researchers.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!