Widespread tumor suppression mechanism stops cancer progression by
interfering with cancer cell metabolism

Date:
August 25, 2021
Source:
The Wistar Institute
Summary:
A Wistar study shows the tumor suppressor Parkin, whose levels
are reduced in different cancer types, causes acute metabolic and
oxidative stress, suppresses mitochondrial trafficking, and blocks
tumor cell movement, reducing primary and metastatic tumor growth.



FULL STORY ========================================================================== According to a study by The Wistar Institute, the tumor suppressor Parkin, whose levels are reduced in different cancer types, causes acute metabolic
and oxidative stress, suppresses mitochondrial trafficking, and blocks
tumor cell movement, reducing primary and metastatic tumor growth. These findings, published today in Science Advances, demonstrate that metabolic
and mitochondrial reprogramming, which are well-established hallmarks
of tumor progression, act as potent drivers of disease.


========================================================================== "We've known for a century that progression from a small, premalignant
lesion to an aggressive tumor and then metastasis is accompanied by
changes in metabolism that allow cancer cells to support increased
energy demands due to continuous growth and adapt to unfavorable microenvironment conditions," said study lead author Dario C. Altieri,
M.D., Wistar president and CEO, director of the Institute's Cancer Center
and the Robert & Penny Fox Distinguished Professor. "Our study provides evidence that reprogramming the metabolic and mitochondrial function
is a cancer-promoting factor opposed by tumor suppression mechanisms,
and we identified one that is relevant to halting several different
types of cancer." Altieri and colleagues studied a gene called Parkin
that is altered in Parkinson's disease. Through a degradation mechanism
called mitophagy, Parkin was known to protect brain cells by facilitating selective removal of damaged mitochondria, the organelles that produce
energy. Previous evidence indicated that Parkin might have a role in
regulating cancer cell metabolism and suppressing tumor growth, but the mechanisms remained elusive.

Researchers re-introduced Parkin in prostate cancer cells and other cancer
cell types that did not express the protein and observed reduced cell
movement and a blocking of invasion. Concordantly, deletion of Parkin
in normal cells increased cell motility.

In vivo, Parkin-expressing prostate cancer cells formed smaller tumors
and had lower metastatic potential. The team found that Parkin expression
was low or undetectable in patient-derived tissue samples and cancer
cell lines and decreased in all the tumor types contained in The Cancer
Genome Atlas database compared with their respective normal counterpart.

A global proteomic study of cancer cells modified to express Parkin
revealed alterations in the protein networks that control cell movement
and metastasis and decreased oncogenic signaling.

Importantly, these effects were independent of Parkin's role in mitophagy
in response to mitochondrial damage. Researchers then asked whether other pathological conditions could activate Parkin. They found that exposing
Parkin- expressing cancer cells to stress conditions such as nutrient deprivation and DNA-damaging agents resulted in a strong increase in
Parkin levels.

Parkin functions as an enzyme that promotes ubiquitination, a process
that modifies proteins to flag them for degradation. Researchers
observed that this function is required for Parkin's tumor suppressive activity. Forced Parkin expression in cancer cells alters ubiquitination
in protein networks that control cell death, mitochondrial function and
glucose metabolism. As a consequence, Parkin interferes with movement
of mitochondria within the cells, which affects their function in tumor progression.

"Our lab has described the role these organelles play in cancer, showing
that changes in mitochondrial size, shape and distribution within
the cells allow for increased cell motility, metastatic dissemination
and other aggressive disease traits," said Ekta Agarwal, Ph.D., first
author of the study and a postdoctoral fellow in the Altieri lab. "This
new study shows how a tumor suppressor pathway opposes mitochondrial
dynamics to counteract cancer progression." Researchers further dissected
the mechanism of Parkin tumor suppression and its role in controlling metabolism, and demonstrated that Parkin expression blocks an enzyme
called transketolase (TKT) that is involved in glycolysis, a metabolic
pathway specifically used by cancer cells to generate energy. This block results in reduced energy production.

TKT also plays a key role in counteracting oxidative stress in the cell.

Therefore, another consequence of its inhibition is buildup of reactive
oxygen species and oxidative stress in the mitochondria, which inhibit mitochondrial function and, in turn, tumor cell motility.

From this study, Parkin emerges as a critical, stress-activated
effector of a tumor suppression pathway that antagonizes malignant cell proliferation and metastatic competence by interfering with the ability
of cancer cells to reprogram their metabolism.

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


========================================================================== Journal Reference:
1. Ekta Agarwal, Aaron R. Goldman, Hsin-Yao Tang, Andrew V. Kossenkov,
Jagadish C. Ghosh, Lucia R. Languino, Valentina Vaira, David
W. Speicher, Dario C. Altieri. A cancer ubiquitome landscape
identifies metabolic reprogramming as target of Parkin tumor
suppression. Science Advances, 2021; 7 (35): eabg7287 DOI:
10.1126/sciadv.abg7287 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210825143111.htm

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