Palmitoylation, a new target for anti-cancer drugs

Date:
April 25, 2022
Source:
Universite' de Gene`ve
Summary:
By developing a tool to visualize the membrane association and
activation status of normal and oncogenic proteins, scientists
have established the basis for innovative drug discovery.



FULL STORY ========================================================================== Peripheral membrane proteins have the particularity of temporarily
binding to cell membranes, a necessary step for them to be able to
fulfil their biological function. To do this, certain enzymes that
catalyse their lipid modification come into action. This process is called "palmitoylation." Some of these proteins can mutate and become oncogenic,
such as the RAS proteins, which are responsible for about one third
of cancers. In order to understand how palmitoylation works and to use
it for therapeutic purposes, scientists from the University of Geneva
(UNIGE), Switzerland, developed a novel tool to visualize this process
in living cells. They have shown that, contrary to what was thought, palmitoylation is possible not only in the Golgi apparatus, the usual site
for protein processing and delivery, but also at the very site where the protein must act, e.g. the plasma membrane. This discovery, to be read
in the journal Nature Communications, paves the way to innovative drug discovery strategies to target very precisely the membrane binding --
and therefore activity -- of oncogenic proteins.


========================================================================== Palmitoylation consist in the introduction of fatty acids into certain
proteins for them to be able to bind to cell membranes. This mechanism
is governed by precise rules, which depend on the sequence of each type
of protein, and on the presence of specialised enzymes. Until now,
the scientific community believed that palmitoylation of peripheral
membrane proteins could only take place in one place in the cell, the
Golgi apparatus.

"Indeed, these proteins are produced in the cytosol -- the cell fluid --
and then 'swim' to the Golgi apparatus, where they are modified before
being transported to where they need to act," explains Gonzalo Solis, researcher in the Department of Cell Physiology and Metabolism at the
UNIGE's Faculty of Medicine, and lead author of this work. "Nevertheless,
we hypothesised the possibility of local palmitoylation, without
passing through the Golgi apparatus. If this is true, it opens up
completely new possibilities for the intervention of this mechanism."
Observing and manipulating proteins To test this hypothesis, the
research team led by Vladimir Katanaev, professor in the Department
of Cell Physiology and Metabolism and at the Centre for Translational
Research in Onco-Haematology at the UNIGE Faculty of Medicine, focused
on a protein called Gao, which is normally located at the plasma membrane
and the Golgi apparatus.

The methodology used is completely new: "We brought the palmitoylating
enzymes to a totally different compartment in the cell, the nuclear
membrane," explains Gonzalo Solis. "Gao was recruited at the nuclear
membrane, allowing us to identify the specific enzyme that palmitoylates
them. We thus confirmed that this process can take place on the very site
the protein is needed." Contrary to usual biochemical methodologies,
the tool developed by Vladimir Katanaev and his team, which they named SwissKASH, is also the first to keep the cell alive and allows for the observation of the process dynamically.

"Until now, there was no alternative to destroying the cell," says
Vladimir Katanaev. "Our method also makes it possible to determine
exactly which protein reacts to which enzyme locally, which is essential
if we want to control this mechanism for therapeutic purposes." A new
drug target Several peripheral membrane proteins, and in particular Ga
subunit proteins and RAS proteins, are susceptible to mutation and thus
acquire an aggressive oncogenic potential. Their oncogenicity depends on
their ability to bind to the plasma membrane; palmitoylation thus plays
a key role in the transformation of a healthy cell into a cancerous one.

"Inhibiting the enzyme that induces palmitoylation, and preventing the oncogenic protein from binding to the plasma membrane, could therefore
defuse its pathogenicity," points out Gonzalo Solis. "We can thus
imagine blocking this specific reaction without unbalancing the whole
system." The scientists will now aim at automatizing this methodology
to study the effect of a whole series of pharmaceutical products on
the palmitoylation of selected oncoproteins, as well as testing their
toxicity on the whole cell.


========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Gonzalo P. Solis, Arghavan Kazemzadeh, Laurence Abrami, Jana
Valnohova,
Cecilia Alvarez, F. Gisou van der Goot, Vladimir L. Katanaev. Local
and substrate-specific S-palmitoylation determines subcellular
localization of Gao. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022- 29685-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220425104905.htm

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