Cargando…
Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis
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...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952940/ https://www.ncbi.nlm.nih.gov/pubmed/31842382 http://dx.doi.org/10.3390/cells8121622 |
_version_ | 1783486536002568192 |
---|---|
author | Nasrullah, Usman Haeussler, Kristina Biyanee, Abhiruchi Wittig, Ilka Pfeilschifter, Josef Eberhardt, Wolfgang |
author_facet | Nasrullah, Usman Haeussler, Kristina Biyanee, Abhiruchi Wittig, Ilka Pfeilschifter, Josef Eberhardt, Wolfgang |
author_sort | Nasrullah, Usman |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6952940 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69529402020-01-23 Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis Nasrullah, Usman Haeussler, Kristina Biyanee, Abhiruchi Wittig, Ilka Pfeilschifter, Josef Eberhardt, Wolfgang Cells Article 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. MDPI 2019-12-12 /pmc/articles/PMC6952940/ /pubmed/31842382 http://dx.doi.org/10.3390/cells8121622 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nasrullah, Usman Haeussler, Kristina Biyanee, Abhiruchi Wittig, Ilka Pfeilschifter, Josef Eberhardt, Wolfgang Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis |
title | Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis |
title_full | Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis |
title_fullStr | Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis |
title_full_unstemmed | Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis |
title_short | Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis |
title_sort | identification of trim25 as a negative regulator of caspase-2 expression reveals a novel target for sensitizing colon carcinoma cells to intrinsic apoptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952940/ https://www.ncbi.nlm.nih.gov/pubmed/31842382 http://dx.doi.org/10.3390/cells8121622 |
work_keys_str_mv | AT nasrullahusman identificationoftrim25asanegativeregulatorofcaspase2expressionrevealsanoveltargetforsensitizingcoloncarcinomacellstointrinsicapoptosis AT haeusslerkristina identificationoftrim25asanegativeregulatorofcaspase2expressionrevealsanoveltargetforsensitizingcoloncarcinomacellstointrinsicapoptosis AT biyaneeabhiruchi identificationoftrim25asanegativeregulatorofcaspase2expressionrevealsanoveltargetforsensitizingcoloncarcinomacellstointrinsicapoptosis AT wittigilka identificationoftrim25asanegativeregulatorofcaspase2expressionrevealsanoveltargetforsensitizingcoloncarcinomacellstointrinsicapoptosis AT pfeilschifterjosef identificationoftrim25asanegativeregulatorofcaspase2expressionrevealsanoveltargetforsensitizingcoloncarcinomacellstointrinsicapoptosis AT eberhardtwolfgang identificationoftrim25asanegativeregulatorofcaspase2expressionrevealsanoveltargetforsensitizingcoloncarcinomacellstointrinsicapoptosis |