Article

TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers

Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Cell (Impact Factor: 33.12). 02/2012; 148(4):639-50. DOI: 10.1016/j.cell.2011.12.033
Source: PubMed

ABSTRACT Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived "TAK1 dependency signature" is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation.

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Available from: Anurag Singh, Feb 13, 2014
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    • "Using LL-Z1640-2, we show that the TGF-β-induced increase in total cytosolic β-catenin levels is attenuated on TAK1 inhibition. This is in line with a recent report showing the positive effect of TAK1 on β-catenin stabilization and nuclear localization in KRAS-dependent colon cancer cells [42]. Furthermore, we extend our findings by demonstrating that TAK1 inhibition reduces transcriptionally active non-phosphorylated β-catenin, linking the TAK1-mediated regulation of β-catenin to functional level. "
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    ABSTRACT: WNT-5A, a key player in embryonic development and post-natal homeostasis, has been associated with a myriad of pathological conditions including malignant, fibroproliferative and inflammatory disorders. Previously, we have identified WNT-5A as a transcriptional target of TGF-β in airway smooth muscle cells and demonstrated its function as a mediator of airway remodeling. Here, we investigated the molecular mechanisms underlying TGF-β-induced WNT-5A expression. We show that TGF-β-activated kinase 1 (TAK1) is a critical mediator of WNT-5A expression as its pharmacological inhibition or siRNA-mediated silencing reduced TGF-β induction of WNT-5A. Furthermore, we show that TAK1 engages p38 and c-Jun N-terminal kinase (JNK) signaling which redundantly participates in WNT-5A induction as only simultaneous, but not individual, inhibition of p38 and JNK suppressed TGF-β-induced WNT-5A expression. Remarkably, we demonstrate a central role of β-catenin in TGF-β-induced WNT-5A expression. Regulated by TAK1, β-catenin is required for WNT-5A induction as its silencing repressed WNT-5A expression whereas a constitutively active mutant augmented basal WNT-5A abundance. Furthermore, we identify Sp1 as the transcription factor for WNT-5A and demonstrate its interaction with β-catenin. We discover that Sp1 is recruited to the WNT-5A promoter in a TGF-β-induced and TAK1-regulated manner. Collectively, our findings describe a TAK1-dependent, β-catenin- and Sp1-mediated signaling cascade activated downstream of TGF-β which regulates WNT-5A induction.
    PLoS ONE 04/2014; 9(4):e94801. DOI:10.1371/journal.pone.0094801 · 3.23 Impact Factor
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    • "A key intermediate in NFκB signaling, TGFβ-activated kinase 1 (TAK1), functions downstream of multiple signaling pathways, regulating cell survival, differentiation, and inflammatory responses [16], and stands as a key IKK-kinase of the canonical NFκB pathway [17]. Chemical and genetic inhibition of TAK1 promotes apoptosis in skin tumors [18] and a subset of colon cancers [19], as well as decreasing chemoresistance in breast and colon cancer cells [20] and chemoresistance and NFκB activity in pancreatic cancer cells in culture [21]. Furthermore, suppression of TAK1 signaling reduces NFκB activation in human head and neck squamous cell carcinoma cell lines [22], ovarian carcinoma cells [23], and breast cancer cell lines [24], and blocks breast cancer cell adhesion, invasion, and metastasis in vitro [25]. "
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    PLoS ONE 01/2014; 9(1):e86470. DOI:10.1371/journal.pone.0086470 · 3.23 Impact Factor
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    • "Blank et al. verified that BMP7 activated the JNK signaling pathway, and MAP3K7 was required for BMP7-mediated JNK activation [51]. In addition, BMP7 could activate MAP3K7 and enhance Wnt-dependent transcription [52]. Expression of BMP7 was indeed consistent with that of MAP3K7 in this study (Figure  3). "
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