Heat-shock protein inhibitors: The new wave of cancer treatment?

By Krishna-Lila Shastri 41391000

Heat-Shock Proteins (HSPs) are a class of proteins that affect numerous processes within plants, animals and indeed humans. HSPs are molecular chaperones; they assist folding newly synthesised proteins into functional forms as well as refolding, disaggregation, and degradation of denatured proteins.

However what has been under investigation in this instance is the role of a particular HSP, Hsp90 in the Fanconi Anaemia pathway (Yamashita et al. 2007). Fanconi Anaemia (FA) is a recessive genetic disease characterised by congenital abnormalities, progressive bone marrow failure and susceptibility to leukaemia and solid tumours.

The FA pathway forms a core complex of proteins which are members of the body’s DNA damage response team. Hsp90 uses its chaperoning abilities to bring the protein FANCA to the core complex. If Hsp90 is inhibited the complex doesn’t form, leading to symptoms similar to those experienced by FA patients.

Since all cells, especially stem cells and tumour cells rely on DNA damage response pathways to continue their growth and survival, compromising the FA pathway for long periods could lead to the failure of tissues that depend on cell replication, as with bone marrow failure in FA patients. Research shows that tumour cells show increased expression and activity of Hsp90 to help them survive under high replicative stress. The paper thus implicates the use of Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), to assist in the treatment of cancer by removing one of the main defences used by tumour cells making them more vulnerable to existing anti-tumour drugs.

References:

Primary source-

Yamashita, T., & Oda, T., & Sekimoto, T. (2007) Hsp90 and the Fanconi Anemia Pathway: A molecular link between protein quality control and the DNA damage response. Cell Cycle, 6(18), 2232-2235

https://www.landesbioscience.com/journals/cc/article/4653

Secondary source-

Pigliucci, M. (2002). Developmental genetics: Buffer zone. Nature, 417, 598-599

http://www.nature.com/nature/journal/v417/n6889/full/417598a.html

Also see

Wikipedia:

http://en.wikipedia.org/wiki/Fanconi_anemia

http://en.wikipedia.org/wiki/Heat_shock_protein

http://en.wikipedia.org/wiki/Chaperone

Molecular Chaperone: A little protein that holds key for an evolution

Molecular chaperones (see figure) are type of proteins that assist fixing of denatured proteins by helping them to refold smoothly. Heat shock protein (Hsp) is one type of such chaperones and they are found universally among living species; from plants; to bacteria; to animals. Recent studies revealed that Hsp also play crucial roles besides defense mechanism against physical damage. They serve as a “genetic buffer” to minimize the effect of random genetic variations by covering these changes; a phenomenon known as “canalization”, which was first coined by Waddington in 1940.
Studies on various model species such as Drosophila melanogaster and Alabidopsis thaliana have proven that inhibition of Hsp90 causes sudden appearance of previously masked phenotypes. This result suggests that Hsp90 is protecting genes from harmful mutations as well as maintaining the potential for evolution, or “evolvability” by accumulating, rather than discarding these variations. Korcsmaros et al. (2007) explains this complex function of Hsp family is made possible by very weak inter-modular links in chaperones. Further, they discuss a possible application for this multi-function of chaperone family to clinical aspects so called “chaperone therapies”. Examples include non-toxic cancer therapy, anti-aging and treatment for general diseases.
Further research on how chaperones act in cellular level will provide important information for understanding the evolutionary biology and also has numbers of potential applications for clinical uses.

Reference

Flatt T., “The Evolutionary Genetics of Canalization” The Quarterly Review of Biology Vol.80 No.3 287-316

Korcsmaros T, Kovacs I.A, Szalay M.S and Csermely P., 2007 “Molecular chaperones: The modular evolution of cellular networks” Journal of Bioscience. Vol.32 441-446

Mitchell-Olds T and Knight C. A., 2002 “Chaperons as Buffering Agents?” Science, Vol 296 2348-2349

Pigliucci M., 2002. “Buffer zone” Nature Vol. 417. (6) 598-599

Stearns S. C., 2002. “Progress on canalization” Proceeding of Natural Academy of Science. Vol.99 (16) 10229-10230

posted by 41135343

Could a single protein buffer genetic variation?

Heat-shock proteins (Hsps) have long been known to perform the vital role of protecting other proteins during periods of stress (i.e. environmental change). In light of recent evidence, however, a specific protein, Hsp90, has been found to help organisms in another, unexpected way: buffering them against genetic change. It does this by masking the effects of new genetic variations. Resistance of organisms to genetic and environmental change has been speculated since the 1940’s and has been termed ‘canalisation’. It was not until experiments involving Drosophila melanogaster and Arabidopsis thaliana that the specific role of Hsp90 in this process was uncovered.

A more recent study questions whether Hsp90 is the sole capacitor responsible for protecting organisms against genetic perturbations. It specifically looked at fruit flies’ bristles and wing sizes. These are complex quantitative traits, which had not been tested in previous studies. The study analysed the effects of inhibiting Hsp90 on these traits. The results proved surprising. It was found that genetic canalisation did not solely depend on Hsp90. This raises the possibility that the involvement of Hsp90 in protecting organisms against genetic change is only contributory. Clearly more extensive research is required in order to further elucidate the exact role of Hsp90 in buffering genetic variation.

Picture: A schematic diagram of Hsp90.

References

Milton, C. C., Huynh, B., Batterham, P., Rutherford, S. L. and Hoffmann, A. A. (2003) Proceedings of the National Academy of Sciences 100, 13396-13401.

Pigliucci, M. (2002) Nature, 417, 598-599.

Queitsch, C., Sangster, T. A. and Lindquist, S. (2002) Nature, 417, 618-624.

Rutherford, S. L. and Lindquist, S. (1998) Nature, 396, 336-342.

Stearns, S. C. (2002) Proceedings of the National Academy of Sciences 99, 10229-10230.

Sangster, T. A., Lindquist, S. and Queitsch, C. (2004) BioEssays, 26, 348-362.

Posted by: s41187089

Topic: Directed Mutation (heat-shock proteins)