TY  - JOUR
A1  - Nasrullah, Usman
A1  - Häußler, Kristina
A1  - Biyanee, Abhiruchi
A1  - Wittig, Ilka
A1  - Pfeilschifter, Josef
A1  - Eberhardt, Wolfgang
T1  - Identification of trim25 as a negative regulator of caspase-2 expression reveals a novel target for sensitizing colon carcinoma cells to intrinsic apoptosis
T2  - Cells
N2  - Colorectal cancer (CRC) is one of the most common cancers that is characterized by a high mortality due to the strong metastatic potential of the primary tumor and the high rate of therapy resistance. Hereby, evasion of apoptosis is the primary underlying cause of reduced sensitivity of tumor cells to chemo- and radiotherapy. Using RNA affinity chromatography, we identified the tripartite motif-containing protein 25 (TRIM25) as a bona fide caspase-2 mRNA-binding protein in colon carcinoma cells. Loss-of-function and gain-of-function approaches revealed that TRIM25 attenuates the protein levels of caspase-2 without significantly affecting caspase-2 mRNA levels. In addition, experiments with cycloheximide revealed that TRIM25 does not affect the protein stability of caspase-2. Furthermore, silencing of TRIM25 induced a significant redistribution of caspase-2 transcripts from RNP particles to translational active polysomes, indicating that TRIM25 negatively interferes with caspase-2 translation. Functionally, the elevation in caspase-2 upon TRIM25 depletion significantly increased the sensitivity of colorectal cells to drug-induced intrinsic apoptosis as implicated by increased caspase-3 cleavage and cytochrome c release. Importantly, the apoptosis-sensitizing effects by transient TRIM25 knockdown were rescued by concomitant silencing of caspase-2, demonstrating a critical role of caspase-2. Inhibition of caspase-2 by TRIM25 implies a survival mechanism that critically contributes to chemotherapeutic drug resistance in CRC.
KW  - caspase-2
KW  - chemotherapy resistance
KW  - colon carcinoma cells
KW  - intrinsic apoptosis
KW  - TRIM25
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/52752
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-527520
SN  - 2073-4409
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 8
IS  - 12, Art. 1622
SP  - 1
EP  - 20
PB  - MDPI
CY  - Basel
ER  -