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Targeting glutamine metabolism sensitizes melanoma cells to TRAIL-induced death
J-Z Qin1, H Xin, B J Nickoloff
1Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
Abstract:
Targeting specific metabolic pathways has emerged for cancer therapeutics. For melanoma, metabolic studies have solely focused on high glucose uptake. By contrast, little is known regarding addiction to glutamine. Using five melanoma lines and two normal cell types, addition of aminooxyacetate (AOA), an inhibitor of glutamate-dependent transaminase regulating glutaminolytic pathway, two lines underwent low levels of apoptosis (>30%), while the other three lines were resistant, as were normal cells to AOA. However, three resistant lines (but not normal cells), became sensitized to undergoing apoptosis when TRAIL was combined with AOA. TRAIL by itself had minimal effects on all cell lines and normal cells, and did not augment AOA-induced killing in the two sensitive melanoma lines. AOA plus TRAIL induced a caspase-dependent apoptotic response. AOA did not influence TRAIL DR4 or DR5 cell surface death receptor levels, but AOA enhanced pro-apoptotic protein levels of Noxa, while reducing pro-survival protein Mcl-1. To verify AOA was targeting glutamine pathway, depletion of glutamine produced similar results, because absence of glutamine sensitized three melanoma lines, but not fibroblasts to killing by TRAIL. Glutamine depletion also led to Noxa induction. These results indicate some lines are addicted to glutamine, and treatment with AOA or glutamine depletion sensitizes melanoma to TRAIL-mediated killing, while sparing normal cells. Future studies are indicated to translate these discoveries to metastatic melanoma as there is currently no treatment available to prolong survival.
Insights
Targeting glutamine metabolism sensitizes melanoma cells to TRAIL-induced apoptosis. Aminooxyacetate (AOA) or glutamine depletion primes resistant melanoma, sparing normal cells, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Metabolic pathway targeting is a key strategy in cancer therapeutics.
- Melanoma research has primarily focused on glucose metabolism, neglecting glutamine's role.
- Glutamine addiction in melanoma remains understudied.
Purpose of the Study:
- To investigate the role of glutamine metabolism in melanoma cell survival.
- To evaluate the efficacy of targeting the glutaminolytic pathway in melanoma.
- To explore combination therapies involving glutamine inhibition and TRAIL.
Main Methods:
- Utilized five melanoma cell lines and two normal cell types.
- Administered aminooxyacetate (AOA), a glutaminolytic pathway inhibitor.
- Assessed apoptosis induction, cell surface death receptor levels, and protein expression (Noxa, Mcl-1).
- Investigated effects of glutamine depletion and TRAIL combination therapy.
Main Results:
- AOA induced apoptosis in two melanoma lines; three were resistant, as were normal cells.
- Combining AOA with TRAIL sensitized resistant melanoma lines to apoptosis, sparing normal cells.
- AOA modulated pro-apoptotic (Noxa) and pro-survival (Mcl-1) protein levels.
- Glutamine depletion mimicked AOA effects, sensitizing melanoma to TRAIL and inducing Noxa.
Conclusions:
- Certain melanoma lines exhibit glutamine addiction.
- Targeting glutamine metabolism with AOA or depletion sensitizes melanoma to TRAIL-induced apoptosis.
- This approach spares normal cells and warrants further investigation for metastatic melanoma treatment.
