TY  - JOUR
A1  - von Bueren, André O.
A1  - Oehler, Christoph
A1  - Shalaby, Tarek
A1  - von Hoff, Katja
A1  - Pruschy, Martin
A1  - Seifert, Burkhardt
A1  - Gerber, Nicolas U.
A1  - Warmuth-Metz, Monika
A1  - Stearns, Duncan
A1  - Eberhart, Charles G.
A1  - Kortmann, Rolf D.
A1  - Rutkowski, Stefan
A1  - Grotzer, Michael A.
T1  - c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients
JF  - BMC Cancer
N2  - Background: 

To study whether and how c-MYC expression determines response to radio-and chemotherapy in childhood medulloblastoma (MB). 

Methods: 

We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio-and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol- 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio-and chemotherapy as examined by neuroradiological imaging. 

Results: 

In DAOY -and to a lesser extent in UW228 -cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation-and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio-(14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively). 

Conclusions: 

c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.
KW  - Induced apoptosis
KW  - Down-regulation
KW  - Childhood medulloblastoma
KW  - Melanoma-cells
KW  - Cisplatin
KW  - Lines
KW  - Gene
KW  - Radiotherapy
KW  - Fibroblasts
KW  - Activation
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134185
VL  - 11
IS  - 74
ER  - 
TY  - JOUR
A1  - Pietro-Garcia, Christian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Fischer, Thomas
A1  - Maier, Carina R.
A1  - Rosenfeldt, Mathias
A1  - Schülein-Völk, Christina
A1  - Klann, Kevin
A1  - Kalb, Reinhard
A1  - Dikic, Ivan
A1  - Münch, Christian
A1  - Diefenbacher, Markus E.
T1  - Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway
JF  - Cell Death and Differentiation
N2  - Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.
KW  - USP28
KW  - Cisplatin
KW  - squamous tumors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-273014
SN  - 1476-5403
VL  - 29
IS  - 3
ER  -