Project 467192

Myristoylation is the modification of proteins by a piece of fat named myristate. The two enzymes named NMT1 and NMT2 transfer myristate are found in healthy cells. The Berthiaume lab discovered a pill named PCLX-001 that inhibits NMT1 and NMT2. It selectively kills blood cancer cells while sparing normal cells (Beauchamp et al. 2020 Nat Commun 11, 5348; doi: 10.1038/s41467-020-18998-1). While studying the mechanism of action of the pill, the Berthiaume lab found that it had not only profound effects on cell survival signalling but also on energy metabolism, mainly in mitochondria (the powerhouse of the cell). Because other researchers recently demonstrated that mitochondrial metabolism is required for cancer cells to spread throughout the body via a process named metastasis (Park et al. 2016 Cell Reports 14, 2154;2165; doi: 10.1016/j.celrep.2016.02.004.), I will investigate if PCLX-001 can abrogate mitochondrial metabolism at the molecular level and prevent metastasis in vivo. More specifically, we will investigate the role of a mitochondrial protein named NDUFAF4 in the process in order to establish a mechanism.In addition to its well-established roles in membrane targeting, I aim to gain new mechanistic insights on myristoylation, this time as a regulator of metabolism, which can impact metastasis. We think PCLX-001 will inhibit metabolism in the mitochondria, which will result in the inhibition of metastasis. This is crucially important and could have a major impact on the treatment of patients with solid tumors since PCLX-001 could be added to numerous chemotherapeutic cocktails in the future to prevent the cancer cells from spreading all over the body, therefore bringing new therapeutic benefits to cancer patients, first in breast cancer and later in lymphoma.