TY  - GEN
TI  - The function of the lipid phosphatase MTMR7 in anti-EGFR
therapy resistance of colorectal cancer (CRC)
A1  - Söhn, Michaela
N2  - Colorectal cancer (CRC) is one of the most common types of cancer worldwide. The most important difficulty of treating this type of cancer, is the intrinsic and/or acquired resistance to chemotherapeutic drugs or targeted therapies. This unresponsiveness is often due to mutations in the KRAS gene, leading to constitutive activation of the RAS signaling pathway and in turn to the proliferation and survival of the tumor cells. The expression of the peroxisome proliferator activated-receptor (PPAR?) is correlated with a good prognosis in CRC patients and it is one of the candidates to inhibit RAS through the upregulation of Ras-inhibitory proteins like PTEN, DOK1
or Caveolin-1.
In this thesis, the relationship between PPAR? and its new binding partner, myotubularin-related protein 7 (MTMR7), was evaluated concerning its inhibitory effect on RAS signaling. The interaction of the two proteins in the cytosol of colorectal cancer cell lines could be verified using
coimmunoprecipitation, proximity ligation assay as well as immunofluorescence co-staining. Furthermore, the expression of PPAR? target genes like TFF3 were upregulated and PPAR?-
responsive-element (PPRE) activity significantly enhanced upon MTMR7 transfection. In contrast, subcellular fractionation revealed no influence of MTMR7 on PPAR? localization. This positive influence of MTMR7 on PPAR? activity was then further elucidated by assessing the impact of MTMR7 overexpression on RAS signaling. Notably, MTMR7 reduced active RAS as well as total protein levels of RAS. This effect could not be prevented by using proteasomal/lysosomal inhibitors (MG132/Chloroquine). Treating the cells with KCl facilitated RAS reduction, whereas amiloride, an epithelial sodium channel blocker prevented its reduction.
Studying the effect of MTMR7 on therapy resistance indicated that a combination therapy using everolimus and sorafenib could not substitute for MTMR7 in vitro. Treating the cells with a MTMR7-peptide, though, reduced cell proliferation significantly. Further investigation of the MTMR7-peptide showed that it is capable to reduce serum response element activation and displayed a tendency of RAS-inhibition.
Conclusively, the tumor suppressor MTMR7 promotes RAS down-regulation, which leads to a reduced ERK 1/2 activation and a transcriptional activation of the nuclear receptor PPAR?. This in turn results in the activation of tumor suppressor genes like CAV1, DOK1 or PTEN. Thus, the MTMR7-PPAR? crosstalk might be a new target for the treatment of colorectal cancer, where mutant KRAS leads to treatment failure of EGFR therapy.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/25716/
Y1  - 2018///
ID  - heidok25716
AV  - public
ER  -