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Polyamine Metabolism and the DHPS/eIF5A Hypusination Axis: From Metabolic Reprogramming to a Therapeutic Achilles'
Kai-Li Liu1, Shuo Zhang1, Feng-Shuo Li1
1College of Medical Engineering, Jining Medical University, Jining 272067, China.
Abstract:
The polyamine metabolic pathway, an evolutionarily conserved nexus integrating nutrient sensing, translation control, and cellular proliferation, is fundamentally rewired in cancer. Melanoma, a malignancy of melanocytes notorious for its metastatic propensity and therapy resistance, exhibits a profound dependency on this pathway, extending beyond mere polyamine abundance to the specialized function of their derivative, hypusine. This review synthesizes cutting-edge insights into the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit as a critical amplifier of oncogenic signaling in melanoma. We dissect its role as a translational rheostat for pro-tumorigenic proteomes, a driver of phenotypic plasticity underpinning invasion and vasculogenic mimicry, and a modulator of the immunosuppressive tumor microenvironment. Moving beyond the classical inhibitor GC7, we explore the emergence of novel allosteric DHPS inhibitors with compelling preclinical efficacy. Finally, we propose a paradigm shift: targeting the DHPS/eIF5A axis represents a strategy to disrupt the "non-oncogene addiction" of melanoma-its reliance on hyperactive translation and adaptive survival mechanisms-offering a promising avenue alongside targeted therapies and immunotherapies.
Insights
Melanoma hijacks the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) pathway to fuel cancer growth and spread. Targeting this hypusination circuit offers a novel therapeutic strategy for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The polyamine metabolic pathway is crucial for cellular functions and is altered in cancer.
- Melanoma, a deadly skin cancer, heavily relies on polyamine metabolism, specifically the hypusination of eIF5A.
- The deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit amplifies oncogenic signaling in melanoma.
Purpose of the Study:
- To review current knowledge on the DHPS/eIF5A hypusination circuit's role in melanoma.
- To explore the circuit's function in promoting tumor progression, invasion, and immune evasion.
- To discuss novel therapeutic strategies targeting this pathway.
Main Methods:
- Literature review of preclinical and clinical studies.
- Analysis of the molecular mechanisms linking DHPS/eIF5A to melanoma.
- Evaluation of emerging DHPS inhibitors.
Main Results:
- The DHPS/eIF5A axis acts as a translational regulator for proteins driving melanoma growth and metastasis.
- Hypusination enhances melanoma's phenotypic plasticity, invasion, and vasculogenic mimicry.
- This pathway also modulates the tumor microenvironment to promote immune suppression.
- Novel allosteric DHPS inhibitors show promising preclinical anti-melanoma activity.
Conclusions:
- Targeting the DHPS/eIF5A axis disrupts melanoma's reliance on hyperactive translation and adaptive survival.
- This approach offers a potential new therapeutic avenue for melanoma, complementing existing treatments.
- Developing DHPS inhibitors could overcome therapy resistance and metastasis in melanoma.
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