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Keywords = Gankyrin

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10 pages, 1757 KB  
Article
The p16 Antagonist Gankyrin Is Overexpressed in Melanocytic Neoplasms
by Sara Moradi and Torsten Ehrig
J. Mol. Pathol. 2022, 3(4), 319-328; https://doi.org/10.3390/jmp3040027 - 21 Nov 2022
Viewed by 2408
Abstract
Gankyrin has a household function in essentially all cells by acting as a chaperone in the assembly of the 26S proteasome, but also functions as a tumor-promoting protein by antagonizing the tumor suppressors retinoblastoma protein, p16, and p53. While gankyrin is overexpressed in [...] Read more.
Gankyrin has a household function in essentially all cells by acting as a chaperone in the assembly of the 26S proteasome, but also functions as a tumor-promoting protein by antagonizing the tumor suppressors retinoblastoma protein, p16, and p53. While gankyrin is overexpressed in many neoplasms outside the skin, its expression in normal skin and cutaneous neoplasms has not been reported previously. We studied the expression of gankyrin in archival human formalin-fixed tissues of cutaneous neoplasms by immunohistochemistry with a monoclonal antibody, and found gankyrin to be overexpressed in 3 of 20 squamous cell carcinomas, none of 10 basal cell carcinomas, 13 of 18 melanocytic nevi, and 7 of 10 melanomas, in many cases with a predominantly nuclear location. Normal epidermal melanocytes expressed gankyrin to a lesser extent than neoplastic melanocytes. The overexpression in the in situ stage of squamous cell carcinoma and in melanocytic nevi suggests that gankyrin acts as a tumor-promoting protein in the early stages of the transition from normal to neoplastic cells. The frequent overexpression of gankyrin in melanocytic neoplasms is significant because it antagonizes the tumor suppressor, p16, which is strongly expressed in melanocytic nevi and some melanomas. Full article
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17 pages, 3094 KB  
Article
Second Generation Small Molecule Inhibitors of Gankyrin for the Treatment of Pediatric Liver Cancer
by Amber M. D’Souza, Manu Gnanamony, Maria Thomas, Peter Hanley, Dipti Kanabar, Pedro de Alarcon, Aaron Muth and Nikolai Timchenko
Cancers 2022, 14(13), 3068; https://doi.org/10.3390/cancers14133068 - 22 Jun 2022
Cited by 2 | Viewed by 3014
Abstract
Background: Gankyrin, a member of the 26S proteasome, is an overexpressed oncoprotein in hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Cjoc42 was the first small molecule inhibitor of Gankyrin developed; however, the IC50 values of >50 μM made them unattractive for clinical use. [...] Read more.
Background: Gankyrin, a member of the 26S proteasome, is an overexpressed oncoprotein in hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Cjoc42 was the first small molecule inhibitor of Gankyrin developed; however, the IC50 values of >50 μM made them unattractive for clinical use. Second-generation inhibitors demonstrate a stronger affinity toward Gankyrin and increased cytotoxicity. The aim of this study was to characterize the in vitro effects of three cjoc42 derivatives. Methods: Experiments were performed on the HepG2 (HBL) and Hep3B (pediatric HCC) cell lines. We evaluated the expression of TSPs, cell cycle markers, and stem cell markers by Western blotting and/or real-time quantitative reverse transcription PCR. We also performed apoptotic, synergy, and methylation assays. Results: The treatment with cjoc42 derivatives led to an increase in TSPs and a dose-dependent decrease in the stem cell phenotype in both cell lines. An increase in apoptosis was only seen with AFM-1 and -2 in Hep3B cells. Drug synergy was seen with doxorubicin, and antagonism was seen with cisplatin. In the presence of cjoc42 derivatives, the 20S subunit of the 26S proteasome was more available to transport doxorubicin to the nucleus, leading to synergy. Conclusion: Small-molecule inhibitors for Gankyrin are a promising therapeutic strategy, especially in combination with doxorubicin. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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