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Small molecule inhibitors that interfere with the protein degradation machinery in cancer cells could be useful as therapeutics.

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A stabilizing strategy to keep cancer cells in check

29 Nov 2019

Bortezomib, a drug that inhibits the ‘waste disposal system’ in animal cells, could treat cancer by indirectly stabilizing a protein that suppresses cell division.

Floor the accelerator and a car speeds up; step on the brakes and it comes to a halt. In cells, an analogous system of ‘accelerators’ and ‘brakes’ exists to regulate cell division. One protein in particular—called p53—has often been described as the ‘brakes’ of mammalian cell division, making sure that cells suffering from irreversible DNA damage do not survive in the body.

Unsurprisingly, the loss of p53 can result in diseases of uncontrolled cell division—cancer is a case in point. Compounds that directly or indirectly stabilize p53 in the cell, leading to elevated p53 levels, are therefore attractive as anticancer drugs. One strategy to stabilize proteins in cells is by blocking the activity of the proteasome—the cellular machinery responsible for getting rid of proteins tagged for degradation.

Researchers led by A*STAR Chief Scientist Sir David Lane thus hypothesized that a proteasome inhibitor called bortezomib could be effective against solid tumors. Bortezomib has already been approved for the clinical treatment of certain blood cancers, but its efficacy against solid tumors remained unclear.

Studying bortezomib in a popular mouse model of benign intestinal tumors (APCmin/+ mice) and mice engrafted with human colorectal cancer cells (known as xenograft models), the team found that bortezomib was highly effective in controlling tumor growth without toxicity. “We found that tumors in the intestines of bortezomib-treated APCmin/+ mice show marked upregulation of p53, p21 and BAX,” said Lane, referring to cellular proteins that arrest cell division and promote cell death.

The researchers further showed that bortezomib caused p53 to enter the nucleus of the cell, where DNA resides. There, p53 activates the expression of genes that function collectively to suppress cell division.

However, Lane and colleagues noted that bortezomib also stabilized p53 in non-cancerous cells of the intestine which are responsible for renewing the intestinal lining. The intestinal lining is shed regularly, so its replacement by intestinal stem cells and another group of dividing cells known as transit amplifying cells is crucial.

“Elevation of p53 and its stabilization by bortezomib may therefore result in gastrointestinal side effects,” said Xue Yuezhen, a Research Scientist in Lane’s lab and the first author of the paper. However, bortezomib was shown to have a short functional half-life in the body, and intestinal stem cells convert between fast-dividing and quiescent states, so a well-timed dose of bortezomib could avoid persistent damage to gastrointestinal tissues, she added.

The researchers intend to study the effects of bortezomib in xenograft models of other types of cancer. They are using the CRISPR/Cas9 gene editing system to create multiple p53-positive and p53-null isogenic cancer cells to establish their xenograft tumors, which will allow them to further explore cancer therapy strategies based on p53 status.

The A*STAR-affiliated researchers contributing to this research are from the p53 Laboratory, the Institute of Medical Biology (IMB) and the Molecular Engineering Lab.

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References

Xue, Y., Barker, N., Hoon, S., He, P., Thakur, T. et al. Bortezomib stabilizes and activates p53 in proliferative compartments of both normal and tumor tissues in vivo. Cancer Research 18, 3744 (2019) | article

About the Researcher

Sir David Lane

Director

p53 Laboratory
Sir David Lane is credited with the landmark discovery of p53 and its role in cancer development. As the Chief Scientist of A*STAR, Lane advises and engages in scientific development across the Biomedical Research Council (BMRC) and the Scientific Engineering Research Council (SERC) at the strategic level. Lane is concurrently the Director of the p53 Laboratory, which primarily focuses on research on protein interactions and how to develop drugs to inhibit such interactions, using p53 as a model system.

This article was made for A*STAR Research by Wildtype Media Group