Autophagy inhibitor will help in the treatment of cancer
A small molecule blocking autophagy in cancer cells has been foundNanonewsnet based on Materials from Harvard Medical School: Long Thought Cancer Target Unraveled
Scientists have identified a small molecule that effectively blocks the protein complex on which the autophagy process depends. Violation of the autophagy process reduces life expectancy and contributes to the development of many diseases. But cancer cells use autophagy to survive under stress. Therefore, a short-term "shutdown" of this mechanism can improve the results of treatment.
The target of a small molecule just discovered by scientists is a complex that regulates the formation of autophagosomes in the cytoplasm of the cell. Autophagosomes are lipid vesicles that recycle old proteins and organelles. They capture the biochemical "garbage" formed in the cell and break it down with the help of hydrolytic enzymes. This process, called autophagy, is essential for cell survival.
"Autophagy helps cells survive stress," explains Junying Yuan, professor of cell biology at Harvard Medical School, senior author of an article in Cell (Liu et al., Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13). "In fact, this is a recycling process, during which old proteins are decomposed into energy sources – amino acids that allow cells to survive in difficult conditions. This is an update mechanism."
Violation of the autophagy process reduces life expectancy and contributes to the development of diseases such as cancer and neurodegeneration. Such disorders include a defect in the Beclin1 gene, which suppresses autophagy in mammalian cells and, according to scientists, increases the risk of prostate and breast cancer.
But, like many other factors in the development of cancer, autophagy can be a double-edged sword.
When cancer cells are exposed to chemotherapy, they use autophagy to survive under stress. Scientists have concluded that in certain cases, a short-term "shutdown" of autophagy can improve the results of treatment.
For many years, pharmaceutical companies have been trying to achieve exactly this – to deprive the cancer cell of a powerful protective mechanism. The problem was to determine the exact target inside the protein complex that regulates the formation of autophagosomes. Professor Yuan and her colleagues managed to uncover one of the key mechanisms of autophagy and identify a small molecule that effectively blocks this process by degrading the protein complex on which it depends. The beclin1 protein encoded by the Beclin1 gene, which scientists have previously associated with autophagy, is part of this complex.
The long–awaited molecule – a specific and powerful inhibitor of autophagy - was named spautin-1 (spautin-1 from “specific and potent autophagy inhibitor-1").
Spautin-1 blocks the activity of USP10, a molecule that provides a kind of "suspension of execution" of the sentence for proteins on death row. Proteins intended for destruction are marked with a marker called ubiquitin, and USP10 often removes this label from the marked proteins, keeping them "alive". Blocking USP10 itself deprives these proteins of protection.
It turned out that Beclin1, in turn, controls the stability of the USP10 protein by regulating its ability to remove the ubiquitin label. In addition, scientists linked this discovery with the results of other studies that established a link between USP10 and p53, the most famous cancer suppressor. Since USP10 mediates the removal of the ubiquitin label from p53, the regulation of this activity of USP10 by Beclin1 is a mechanism for controlling the level of p53.
"The knockdown of Beclin1, which is carried out by our small molecule, leads to a knockdown of USP10 and, sequentially, to a knockdown of p53," explains Professor Yuan. "They are all links in the same chain."
This explains earlier observations that mammals with a defect in the Beclin1 gene have an increased risk of developing cancer. When the amount of beclin1 protein is reduced, the amount of p53 is also reduced, and cancer thrives. However, complete deletion of the Beclin1 gene leads to cell death.
The long–standing goal of pharmaceutical companies – to "turn off" autophagy in cancer cells - can be achieved by inactivating the protein complex (Vps34) responsible for the formation of autophagosomes.
The small molecule spautin-1 found by scientists makes it possible to achieve this goal by blocking the activity of two peptidases – USP10 and USP13, the target of which is the tumor suppressor Beclin1 – a subunit of the Vps34 complex.
Peptidases USP10 and USP13 usually remove the ubiquitin label from Beclin1, thereby maintaining the activity of the protein complex.
Blocking the USP10 and USP13 themselves with spautin-1 leaves Beclin1 unprotected. (Fig. cell.com )
This finding suggests that selective targeting of autophagy in cancer treatment may be of great benefit to patients.
Professor Yuan is currently engaged in organizing cooperation with scientists from the pharmaceutical company Roche (Basel, Switzerland) and BioBay Biotechnopark (Suzhou, China) in order to develop medicines based on the results of her research.
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30.11.2011