MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma

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Räsänen , K , Dang , K X , Mustonen , H , Ho , T H , Lintula , S , Koistinen , H , Stenman , U-H , Haglund , C & Stenman , J 2018 , ' MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma ' , Molecular oncology , vol. 12 , no. 2 , pp. 224-238 . https://doi.org/10.1002/1878-0261.12160

Title: MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma
Author: Räsänen, Kati; Dang, Kien X.; Mustonen, Harri; Ho, Tho H.; Lintula, Susanna; Koistinen, Hannu; Stenman, Ulf-Håkan; Haglund, Caj; Stenman, Jakob
Contributor organization: Medicum
Department of Clinical Chemistry and Hematology
Clinicum
University of Helsinki
Department of Surgery
II kirurgian klinikka
Department of Diagnostics and Therapeutics
Translational Cancer Biology (TCB) Research Programme
Research Programs Unit
Department of Pathology
HUS Abdominal Center
HUSLAB
Date: 2018-02
Language: eng
Number of pages: 15
Belongs to series: Molecular oncology
ISSN: 1878-0261
DOI: https://doi.org/10.1002/1878-0261.12160
URI: http://hdl.handle.net/10138/233488
Abstract: The mitogen-activated protein kinase (MAPK) pathway plays a central role in colorectal cancers (CRC). In particular, BRAF V600E-mutant tumors, which represent around 10% of CRCs, are refractory to current therapies. Overexpression and secretion of serine peptidase inhibitor Kazal type 1 (SPINK1) are observed in around 50% of CRCs, and its serum level can be used as a biomarker for poor prognosis. Utilizing a recently developed extendable blocking probe assay, we analyzed the BRAF mutation status in a CRC patient cohort (N=571) using tissue-derived RNA as the starting material. From the same RNA samples, we measured the relative SPINK1 expression levels using a quantitative real-time PCR method. Expression of mutant BRAF V600E correlated with poor prognosis, as did low expression of SPINK1 mRNA. Further, BRAF V600E correlated negatively with SPINK1 levels. In order to investigate the effect of MAPK pathway-targeted therapies on SPINK1 secretion, we conducted invitro studies using both wild-type and V600E CRC cell lines. BRAF inhibitor vemurafenib, and subsequent MAPK pathway inhibitors trametinib and SCH772984, significantly increased SPINK1 secretion in V600E CRC cell lines Colo205 and HT-29 with a concomitant decrease in trypsin-1 and -2 secretion. Notably, no SPINK1 increase or trypsin-1 decrease was observed in BRAF wild-type CRC cell line Caco-2 in response to MAPK pathway inhibitors. In further mechanistic studies, we observed that only trametinib was able to diminish completely both MEK and ERK phosphorylation in the V600E CRC cells. Furthermore, the key regulator of integrated stress response, activating transcription factor 4 (ATF-4), was downregulated both at mRNA and at protein level in response to trametinib treatment. In conclusion, these data suggest that sustained inhibition of not only MAPK pathway activation, but also ATF-4 and trypsin, might be beneficial in the therapy of BRAF V600E-mutant CRC and that SPINK1 levels may serve as an indicator of therapy response.
Subject: biomarker
BRAF V600E
colorectal cancer
inhibitor
SPINK1
trametinib
PROGNOSTIC MARKER
CANCER
RESISTANCE
TATI
PROLIFERATION
TRYPSINOGEN-2
ACTIVATION
EXPRESSION
KINASES
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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