Flipping a metabolic switch to slow tumor growth

Date:
August 12, 2020
Source:
University of California - San Diego
Summary:
The enzyme serine palmitoyl-transferase can be used as a
metabolically responsive 'switch' that decreases tumor growth,
according to a new study.



FULL STORY ==========================================================================
The enzyme serine palmitoyl-transferase can be used as a metabolically responsive "switch" that decreases tumor growth, according to a new
study by a team of San Diego scientists, who published their findings
Aug. 12 in the journal Nature.


==========================================================================
By restricting the dietary amino acids serine and glycine, or
pharmacologically targeting the serine synthesis enzyme phosphoglycerate dehydrogenase, the team induced tumor cells to produce a toxic lipid
that slows cancer progression in mice. Further research is needed to
determine how this approach might be translated to patients.

Over the last decade researchers have learned that removing the amino
acids serine and glycine from animal diets slows the growth of some
tumors. However, most research teams have focused on how these diets
impact epigenetics, DNA metabolism, and antioxidant activity. In contrast,
the researchers from the University of California San Diego and the Salk Institute for Biological Studies identified a dramatic impact of these interventions on tumor lipids, particularly those found on the surface
of cells.

"Our work highlights the beautiful complexity of metabolism as well as
the importance of understanding physiology across diverse biochemical
pathways when considering such metabolic therapies," said Christian
Metallo, a professor of bioengineering at the Jacobs School of Engineering
at UC San Diego and the paper's corresponding author.

In this case, serine metabolism was the researchers' focus. The enzyme
serine palmitoyl-transferase, or SPT, typically uses serine to make fatty molecules called sphingolipids, which are essential for cell function. But
if serine levels are low, the enzyme can act "promiscuously" and use a different amino acid such as alanine, which results in the production
of toxic deoxysphingolipids.

The team decided on this research direction after examining the
affinity that certain enzymes have to serine and comparing them to the concentration of serine in tumors. These levels are known as Km or the Michaelis constant, and the numbers pointed to SPT and sphingolipids.

"By linking serine restriction to sphingolipid metabolism, this finding
may enable clinical scientists to better identify which patients' tumors
are most sensitive to serine-targeting therapies," Metallo said.

These toxic deoxysphingolipids are most potent at decreasing the growth
of cells in "anchorage-independent" conditions -- a situation where
cells cannot easily adhere to surfaces that better mimics tumor growth
in the body. Further studies are necessary to better understand the
mechanisms through which deoxysphingolipids are toxic to cancer cells
and what effects they have on the nervous system.

In the Nature study, the research team fed a diet low on serine and
glycine to xenograft model mice. They observed that SPT turned to alanine
to produce toxic deoxysphingolipids instead of normal sphingolipids. In addition, researchers used the amino-acid based antibiotic myriocin to
inhibit SPT and deoxysphingolipid synthesis in mice fed low serine and
glycine diets and found that tumor growth was improved.

Depriving an organism of serine for long periods of time leads to
neuropathy and eye disease, Metallo pointed out. Last year, he co-lead
an international team that identified reduced levels of serine and
accumulation of deoxysphingolipids as a key driver of a rare macular
disease called macular telangiectasia type 2, or MacTel. The work
was published in the New England Journal of Medicine. However, serine restriction or drug treatments for tumor therapy would not require the prolonged treatments that induce neuropathy in animals or age-related
diseases.

This work was supported by the National Institutes of Health (R01CA188652
and R01CA234245; U54CA132379), a Camille and Henry Dreyfus Teacher-Scholar Award, the National Science Foundation Faculty Early Career Development (CAREER) Program, the Helmsley Center for Genomic Medicine and funding
from Ferring Foundation. This work was also supported by NIH grants to
the Salk Institute Mass Spectrometry Core (P30CA014195, S10OD021815).


========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Ioana
Patringenaru. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Thangaselvam Muthusamy, Thekla Cordes, Michal K. Handzlik, Le
You, Esther
W. Lim, Jivani Gengatharan, Antonio F. M. Pinto, Mehmet G. Badur,
Matthew J. Kolar, Martina Wallace, Alan Saghatelian, Christian
M. Metallo. Serine restriction alters sphingolipid diversity to
constrain tumour growth.

Nature, 2020; DOI: 10.1038/s41586-020-2609-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200812115255.htm

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