A sugar hit to help destroy cancer cells
Chemical engineers have unlocked a fatal vulnerability in many cancer
cells -- sugar inflexibility

Date:
June 17, 2020
Source:
University of Southern California
Summary:
Like any cells in the body, cancer cells need sugar -- namely
glucose - - to fuel cell proliferation and growth. However,
researchers have unlocked a weakness in a common type of cancer
cell: sugar inflexibility.

That is, when cancer cells are exposed to a different type of
sugar - galactose - the cells can't adapt, and will die.



FULL STORY ==========================================================================
Like any cells in the body, cancer cells need sugar - namely glucose -- to
fuel cell proliferation and growth. Cancer cells in particular metabolize glucose at a much higher rate than normal cells. However researchers from
USC Viterbi's Mork Family Department of Chemical Engineering and Materials Science have unlocked a weakness in a common type of cancer cell: sugar inflexibility. That is, when cancer cells are exposed to a different
type of sugar -- galactose - - the cells can't adapt, and will die.


==========================================================================
The discovery, which could have important implications for new metabolic treatments for cancer, was led by Dongqing Zheng, a PhD student in the
lab of Nicholas Graham, assistant professor of chemical engineering and materials science. The research was recently published in the Journal
of Cell Science.

The paper describes how oncogenes, the genes that cause cancer, can
also lead cancer cells to become inflexible to changes in their sugar
supply. Normally, cells grow by metabolizing glucose, but most normal
cells can also grow using galactose. However, the team discovered that
cells possessing a common cancer- causing gene named AKT cannot process galactose, and therefore they die when exposed to this type of sugar.

Zheng said that galactose is quite structurally similar to the glucose
which helps cancer cells thrive, but that it has some differences. Graham
said that exposing cells to galactose forces them to do more oxidative metabolism, where oxygen is used to convert sugars into energy, as opposed
to glycolytic metabolism, where energy is derived from glucose. Normal
cells can metabolize both glucose and galactose, but cancer cells that
with an activated AKT signaling pathway, commonly found in breast cancer
cells, cannot.

"We hadn't seen research looking at galactose in a cancer context,
to see whether specific mutations can cause cancer cause cells to be
better or worse at managing that switch between glycolytic and oxidative metabolism," Graham said.

Zheng said that the discovery did not mean that galactose itself would
be an effective treatment for AKT-type cancer cells, but that it did
uncover a fundamental flaw in these cells, whereby the oxidative state
leads to cell death.



========================================================================== "What we're trying to do is to use a systems approach to understand this,
so we can use some type of targeted drug or gene therapy that can induce a similar effect and force the cell into this oxidative state," Zheng said.

"Galactose is a model system that we're using to uncover these
vulnerabilities in cells that would then lead to future drug development," Graham said. "Our lab will focus on trying to use drugs specifically
to do that." The team's findings also showed that while the oxidative
process brought on by galactose did result in cell death in AKT-type
cancer cells, when the cells were given a different genetic mutation,
MYC, the galactose did not kill the cells.

"So if you had a drug that could inhibit glycolysis, you would give it
to a patient that had an AKT mutation," Graham said. "But you wouldn't
give it to a patient that had an MYC mutation, because it wouldn't work theoretically for those MYC cells." The researchers also discovered
after around 15 days in galactose, some cancer cells started to reoccur.



========================================================================== "Maybe there is a small sub population that are resistant to the
galactose," Zheng said. "The other possibility is that some cancer cells
are very resilient and they adapt and reprogram themselves after two weeks exposed to the galactose treatment." The systems biology approach to
cancer treatment is different to traditional treatments like chemotherapy
and radiation therapy in that it targets metabolic processes in cancer
cells. It aims to identify drugs without a lot of the side effects
of traditional chemotherapies that also kill healthy cells, leading to
adverse effects such as hair loss. However some resurgence is common in a
lot of targeted metabolic treatments for cancer, which demonstrate strong initial results before a partial recurrence of the cells. Graham said
that AKT tumors can potentially be targeted using a metabolic treatment
like this, in order to initially shrink the tumor, but that the treatment
would need to be accompanied by another treatment in a drug cocktail to
prevent recurrence and protect against cancer cells mutating and adapting.

Zheng and Graham said the latest research would not have been possible
without the work of undergraduate students Jonathan Sussman (biomedical engineering) and Matthew Jeon (chemical engineering and materials
science), who assisted with cell counting tasks and proteomics - the
study of the proteins involved in the cancer cells' metabolism.

Graham said that moving forward, the team's biggest challenge is to
figure out which types of combination treatments to apply to test in
cancer cells with the AKT gene, to lead to more effective therapeutics.

The research was funded by the Margaret E. Early Medical Research Trust,
the Rose Hills Foundation, the USC Provost's Office and the USC Viterbi
School of Engineering.


========================================================================== Story Source: Materials provided by
University_of_Southern_California. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Dongqing Zheng, Jonathan H. Sussman, Matthew P. Jeon, Sydney
T. Parrish,
Melanie A. MacMullan, Alireza Delfarah, Nicholas A. Graham. AKT
but not MYC promotes reactive oxygen species-mediated cell death
in oxidative culture. Journal of Cell Science, 2020; 133 (7):
jcs239277 DOI: 10.1242/ jcs.239277 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200617100430.htm

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