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: 32.24). 02/2012; 148(4):639-50. DOI: 10.1016/j.cell.2011.12.033
Source: PubMed


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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    • "Recent studies have shown that TAK1 might be a key oncogene that is over-expressed and/or over-activated in many tumors. TAK1 inhibition could induce cancer cell apoptotic death [9] [10] [11] [12]. Thus, TAK1 may be an effective target for cancer intervention [7] [9] [10]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is common renal malignancy within poor prognosis. TGF-β-activated kinase 1 (TAK1) plays vital roles in cell survival, apoptosis-resistance and carcinogenesis through regulating nuclear factor-κB (NF-κB) and other cancer-related pathways. Here we found that TAK1 inhibitors (LYTAK1, 5Z-7-oxozeanol (5Z) and NG-25) suppressed NF-κB activation and RCC cell (786-O and A489 lines) survival. TAK1 inhibitors induced apoptotic cytotoxicity against RCC cells, which was largely inhibited by the broad or specific caspase inhibitors. Further, shRNA-mediated partial depletion of TAK1 reduced 786-O cell viability whiling activating apoptosis. Significantly, TAK1 was over-expressed in human RCC tissues, and its level was correlated with phosphorylated NF-κB. Finally, kinase inhibition or genetic depletion of TAK1 enhanced the activity of vinblastine sulfate (VLB) in RCC cells. Together, these results suggest that TAK1 may be an important oncogene or an effective target for RCC intervention.
    Preview · Article · Sep 2014 · Biochemical and Biophysical Research Communications
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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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    • "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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