E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma.
Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.
National Cancer Institute, Vilnius, Lithuania.
Kristina
K
Bielskienė
Department of Biochemistry and Molecular Biology, Vilnius University, Vilnius, Lithuania. Electronic address: lida.bagdoniene@gf.vu.lt.
Lida
L
Bagdonienė
National Cancer Institute, Vilnius, Lithuania.
Julija
J
Mozūraitienė
National Cancer Institute, Vilnius, Lithuania.
Birutė
B
Kazbarienė
National Cancer Institute, Vilnius, Lithuania.
Ernestas
E
Janulionis
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D044783:F-Box Proteins / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D058990:Molecular Targeted Therapy; D011379:Prognosis; D059748:Proteolysis / Q000187:drug effects; D012878:Skin Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D044767:Ubiquitin-Protein Ligases
F-box proteins; Melanoma; RING proteins; SCF E3 ligases; Ubiquitin ligases