TY  - JOUR
A1  - Houben, Roland
A1  - Celikdemir, Büke
A1  - Kervarrec, Thibault
A1  - Schrama, David
T1  - Merkel cell polyomavirus: infection, genome, transcripts and its role in development of Merkel cell carcinoma
JF  - Cancers
N2  - The best characterized polyomavirus family member, i.e., simian virus 40 (SV40), can cause different tumors in hamsters and can transform murine and human cells in vitro. Hence, the SV40 contamination of millions of polio vaccine doses administered from 1955–1963 raised fears that this may cause increased tumor incidence in the vaccinated population. This is, however, not the case. Indeed, up to now, the only polyomavirus family member known to be the most important cause of a specific human tumor entity is Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma (MCC). MCC is a highly deadly form of skin cancer for which the cellular origin is still uncertain, and which appears as two clinically very similar but molecularly highly different variants. While approximately 80% of cases are found to be associated with MCPyV the remaining MCCs carry a high mutational load. Here, we present an overview of the multitude of molecular functions described for the MCPyV encoded oncoproteins and non-coding RNAs, present the available MCC mouse models and discuss the increasing evidence that both, virus-negative and -positive MCC constitute epithelial tumors.
KW  - Merkel cell carcinoma
KW  - polyomavirus
KW  - T antigen
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305021
SN  - 2072-6694
VL  - 15
IS  - 2
ER  - 
TY  - JOUR
A1  - Houben, Roland
A1  - Alimova, Pamela
A1  - Sarma, Bhavishya
A1  - Hesbacher, Sonja
A1  - Schulte, Carolin
A1  - Sarosi, Eva-Maria
A1  - Adam, Christian
A1  - Kervarrec, Thibault
A1  - Schrama, David
T1  - 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone inhibits MCPyV T antigen expression in Merkel cell carcinoma independent of Aurora kinase A
JF  - Cancers
N2  - Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT) — a reported inhibitor of Aurora kinase A — as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate that β-catenin — a transcription factor repressed by active glycogen synthase kinase 3 (GSK3) — is activated by PHT, suggesting that PHT bears a hitherto unreported inhibitory activity against GSK3, a kinase known to function in promoting TA transcription. Indeed, applying an in vitro kinase assay, we demonstrate that PHT directly targets GSK3. Finally, we demonstrate that PHT exhibits in vivo antitumor activity in an MCC xenograft mouse model, suggesting a potential use in future therapeutic settings for MCC.
KW  - Merkel cell carcinoma
KW  - polyomavirus
KW  - large T antigen
KW  - phthalazinone pyrazole
KW  - glycogen synthase kinase 3
KW  - GSK3
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313547
SN  - 2072-6694
VL  - 15
IS  - 9
ER  - 
TY  - JOUR
A1  - Sarma, Bhavishya
A1  - Willmes, Christoph
A1  - Angerer, Laura
A1  - Adam, Christian
A1  - Becker, Jürgen C.
A1  - Kervarrec, Thibault
A1  - Schrama, David
A1  - Houben, Roland
T1  - Artesunate affects T antigen expression and survival of virus-positive Merkel cell carcinoma
JF  - Cancers
N2  - Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate — a drug used to treat malaria — has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.
KW  - artesunate
KW  - Merkel cell carcinoma
KW  - MCC
KW  - polyomavirus
KW  - ferroptosis
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203851
SN  - 2072-6694
VL  - 12
IS  - 4
ER  -