ArticleMolecular cancer research : MCR2015
Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway.
Article in Molecular cancer research : MCR, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 80 citations in OpenAlex.
- A functional food approach: probiotic-fermentedFrontiers in nutrition · 2026Article
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.FASEB bioAdvances · 2025Review
- Integrated Approach of Machine Learning and High-Throughput Screening to Identify Chemical Probe Candidates Targeting Aldehyde Dehydrogenases.ACS pharmacology & translational science · 2025Article
- Proline Metabolism in Cancer: Emerging Roles in Redox Homeostasis and Therapeutic Opportunities.Cancers · 2025Review
- ALDH18A1 has carcinogenic functions and regulates alternative splicing events of DNA repair-related genes in esophageal carcinoma cells.Scientific reports · 2025Article
- P5CS deacetylation mediated by SIRT2 facilitates tumor growth by enhancing mitochondrial respiration in hepatocellular carcinoma.Oncogene · 2025Article
- Age-Related Meat Flavor Precursors of Naturally Grazed Sunit Sheep: Metabolomics and Transcriptomics Approaches.Foods (Basel, Switzerland) · 2025Article
- Targeting the glutamine-arginine-proline metabolism axis in cancer.Journal of enzyme inhibition and medicinal chemistry · 2024Review
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation.Cancer & metabolism · 2024Article
- Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.Communications biology · 2024Article
- Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.Nature metabolism · 2023Article
- Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer.Cancers · 2023Review
- In Vitro Evaluation of ALDH1A3-Affinic Compounds on Breast and Prostate Cancer Cell Lines as Single Treatments and in Combination with Doxorubicin.Current issues in molecular biology · 2023Article
- Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets.MedComm · 2023Review
- Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development.International journal of molecular sciences · 2022Article
- Dysbiosis of skin microbiome and gut microbiome in melanoma progression.BMC microbiology · 2022Article
- Investigation of the effects of overexpression of jumping translocation breakpoint (JTB) protein in MCF7 cells for potential use as a biomarker in breast cancer.American journal of cancer research · 2022Article
- Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledMany processes are deregulated in melanoma cells and one of those is protein production. Although much is known about protein synthesis in cancer cells, effective ways of therapeutically targeting this process remain an understudied area of research. A process that is upregulated in melanoma compared with normal melanocytes is proline biosynthesis, which has been linked to both oncogene and tumor suppressor pathways, suggesting an important convergent point for therapeutic intervention. Therefore, an RNAi screen of a kinase library was undertaken, identifying aldehyde dehydrogenase 18 family, member A1 (ALDH18A1) as a critically important gene in regulating melanoma cell growth through proline biosynthesis. Inhibition of ALDH18A1, the gene encoding pyrroline-5-carboxylate synthase (P5CS), significantly decreased cultured melanoma cell viability and tumor growth. Knockdown of P5CS using siRNA had no effect on apoptosis, autophagy, or the cell cycle but cell-doubling time increased dramatically suggesting that there was a general slowdown in cellular metabolism. Mechanistically, targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis, which could be reversed with proline supplementation. Thus, targeting ALDH18A1 in melanoma can be used to disrupt proline biosynthesis to limit cell metabolism thereby increasing the cellular doubling time mediated through the GCN2 pathway. IMPLICATIONS: This study demonstrates that melanoma cells are sensitive to disruption of proline synthesis and provides a proof-of-concept that the proline synthesis pathway can be therapeutically targeted in melanoma tumors for tumor inhibitory efficacy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.