Abstract
Traf2- and Nck-interacting kinase (TNIK) is one of the germinal center kinase family members involved in cytoskeleton organization and neuronal dendrite extension. Emerging evidence supports that TNIK is essential for activation of WNT signaling pathway in colon cancer growth. To search for novel genetic aberrations that drive carcinogenesis, we performed microarray-based comparative hybridization assay for gene copy number variations in primary tumor samples. Our data showed that TNIK gene was amplified in 7% (8/106) of Chinese gastric cancer patients. Theses amplifications were confirmed by fluorescence in situ hybridization analysis. PAMC82 human gastric cancer and T47D human breast cancer cell lines with TNIK amplification were identified to further understand the function of TNIK gene amplification. RNA-interference-mediated silencing of TNIK resulted in significant inhibition of cell growth and induction of cell death in TNIK-amplified, but not in TNIK-non-amplified, cell lines tested. This selective sensitivity to the TNIK inhibition was also observed under the effect of a small-molecule TNIK inhibitor. Furthermore, our data indicated that TNIK's role in gastric cancer growth was not dependent on Wnt signaling but rather was involved in AKT activation and cell autophagy. Together, our results suggest that TNIK is a novel therapeutic target in gastric cancer and TNIK amplification can be potentially used for patient selection.
Highlights
Traf2- and Nck-interacting kinase (TNIK) is a member of germinal center kinases possessing an N-terminal kinase domain
It was first identified as a tumor necrosis factor receptor–associated factor-2 and Nck-interacting kinase, which can activates the c-Jun N-terminal kinase (JNK) pathway when transfected into cells
TNIK amplification is not associated with activation of Wnt signaling
Summary
TNIK is a member of germinal center kinases possessing an N-terminal kinase domain. It was first identified as a tumor necrosis factor receptor–associated factor-2 and Nck-interacting kinase, which can activates the c-Jun N-terminal kinase (JNK) pathway when transfected into cells. In addition, TNIK can physically associate with Rap to regulate cytoskeleton organization and cell spreading. By taking a proteomics approach, Mahmoudi et al. observed TNIK as a T-cell transcription factor 4 (TCF4) interactor in the proliferative crypts of mouse small intestine. In the Wnt-activated intestinal crypts and colorectal cancer cells, TNIK is localized in the nuclei and functions as transcription activator to promoters of Wnt target genes in a b-catenin-dependent manner. Exogenous expression of TNIK kinase inactive mutants abrogates TCF/LEF (lymphoid enhancer-binding factor)driven transcription, suggesting that its kianse activity is essential in TCF/LEF-driven transcriptional activation of Wnt signaling. The growth inhibition could be rescued by reintroduction of the catalytic domain of TNIK, confirming the requirement of its enzymatic activity in maintenance of colorectal cancer growth. Together, data from this investigation suggest that TNIK is a potential target for the development of a pharmacological kinase inhibitor for the treatment of colorectal cancer with aberrant Wnt signaling. Our results by using siRNAmediated gene silencing and a small-molecule TNIK inhibitor suggest that TNIK is a potential target in solid tumors beyond colorectal cancer
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