Enzymatic targets for anticancer therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Smoking tobacco is causally related to the development of several different types of cancer. Many types of cancers, including those caused by tobacco use, contain mutations leading to the activation of one of the Ras proteins. The Ras proteins are located along the inner surface of the plasma membrane and transmit signals from growth factor receptors to the cell nucleus, leading to the transcription of genes involved in cell growth. Activated Ras proteins transmit these growth signals in a continuous and uncontrolled fashion, leading to the development of cancer. 
 
 
 
 
 
 Controlling the unregulated Ras activity in Ras-induced cancers would be highly desirable because it would offer a potential way to treat these cancers. One potential method of interfering with Ras activity is to block the enzymes that normally modify the Ras proteins. The enzymatic modification of Ras proteins is important in allowing these proteins to reach their proper location along the plasma membrane.
 
 
 
 
 
 After synthesis the Ras proteins undergo three sequential processing events. First, a lipid (prenyl group) is added to a cysteine amino acid residue four amino acids from the end of the protein. Second, the last three amino acids of the protein are clipped off. Third, the newly exposed, lipidated cysteine is modified with a methyl group by an enzyme called isoprenylcysteine carboxyl methyltransferase (Icmt). Each of these modifications assists in directing the Ras proteins to membrane surfaces within cells. The anchoring of the Ras proteins to the plasma membrane is crucial for their function. 
 
 
 
 
 
 Pharmaceutical drugs that block one of the “lipidation” enzymes (farnesyltransferase, or FTase) interfere with the membrane targeting of Ras proteins and interfere with Ras function. Unfortunately, K-Ras (a version of Ras most often implicated in human cancers) can be lipidated by another enzyme, raising doubts about whether those FTase inhibitor drugs will actually be effective. Remarkably, no one has ever used mouse genetic models to define the biological consequences of FTase deficiency. During the next 3 years, one goal of my project will be to define the consequences of complete absence of the FTase enzyme. I will generate genetically modified mice that harbor a conditional knockout version of the gene that encodes FTase. The development of this mutant mouse will make it possible to excise (knockout) the gene for FTase in specific tissues or in cells from the mice. Excision of the FTase gene will allow me to determine whether FTase deficiency has a significant impact on the growth of K-Ras-induced tumors. 
 
 
 
 
 
 
 
 A second goal of my project will be to explore the possibility that the absence of Icmt activity will result in a significant downregulation of Ras function and inhibition of Ras-induced tumors. During my postdoctoral fellowship, I generated mice and cell lines lacking the Icmt gene. The Ras proteins were profoundly mislocalized in Icmt-deficient cells, and only a very small percentage of the Ras proteins reached their proper location along the plasma membrane. Icmt-deficient fibroblasts displayed a substantial growth defect. Preliminary experiments have indicated that Icmt-deficient cells are resistant to cancerous growth by activated forms of the Ras proteins. These preliminary results were extremely intriguing. To pursue this issue further, I plan to generate another mutant version of the Icmt gene, one that will allow me to excise the Icmt gene from living cells and tissues, similar to the one described for FTase above. This experimental approach will make it possible to compare phenotypes of “normal Icmt expression” and “Icmt-deficiency” and to do so in the very same cell line. These gene-excision experiments will allow me to more precisely define the effects of Icmt deficiency on cancerous cell growth. Ultimately, my work could lead to the development of new ways to treat tobacco-related cancers.