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IKK? phosphorylates kindlin-2 to induce invadopodia formation and promote colorectal cancer metastasis.

ABSTRACT: Invadopodia formation is a key driver of cancer metastasis. The noncanonical IkB-related kinase IKK? has been implicated in cancer metastasis, but its roles in invadopodia formation and colorectal cancer (CRC) metastasis are unclear. Methods: Immunofluorescence, gelatin-degradation assay, wound healing assay and transwell invasion assay were used to determine the influence of IKK? over-expression, knockdown and pharmacological inhibition on invadopodia formation and the migratory and invasive capacity of CRC cells in vitro. Effects of IKK? knockdown or pharmacological inhibition on CRC metastasis were examined in mice. Immunohistochemistry staining was used to detect expression levels of IKK? in CRC patient tissues, and its association with prognosis in CRC patients was also analyzed. Immunoprecipitation, western blotting and in vitro kinase assay were constructed to investigate the molecular mechanisms. Results: IKK? co-localizes with F-actin and the invadopodia marker Tks5 at the gelatin-degrading sites of CRC cells. Genetic over-expression/knockdown or pharmacological inhibition of IKK? altered invadopodia formation and the migratory and invasive capacity of CRC cells in vitro. In vivo, knockdown or pharmacological inhibition of IKK? significantly suppressed metastasis of CRC cells in mice. IKK? knockdown also inhibited invadopodia formation in vivo. Clinical investigation of tumor specimens from 191 patients with CRC revealed that high IKK? expression correlates with metastasis and poor prognosis of CRC. Mechanistically, IKK? directly binds to and phosphorylates kindlin-2 at serine 159; this effect mediates the IKK?-induced invadopodia formation and promotion of CRC metastasis. Conclusions: We identify IKK? as a novel regulator of invadopodia formation and a unique mechanism by which IKK? promotes the metastasis of CRC. Our study suggests that IKK? is a potential target to suppress CRC metastasis.

SUBMITTER: Liu G

PROVIDER: S-EPMC7019159 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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IKKε phosphorylates kindlin-2 to induce invadopodia formation and promote colorectal cancer metastasis.

Liu Ge G Bao Yantao Y Liu Chaohua C Zhu Qinchang Q Zhao Lin L Lu Xiaopeng X Zhu Qian Q Lv Yafei Y Bai Feng F Wen He H Sun Yujie Y Zhu Wei-Guo WG

Theranostics 20200116 5

Invadopodia formation is a key driver of cancer metastasis. The noncanonical IkB-related kinase IKKε has been implicated in cancer metastasis, but its roles in invadopodia formation and colorectal cancer (CRC) metastasis are unclear. <b>Methods</b>: Immunofluorescence, gelatin-degradation assay, wound healing assay and transwell invasion assay were used to determine the influence of IKKε over-expression, knockdown and pharmacological inhibition on invadopodia formation and the migratory and inva ...[more]

PMID: 32104508

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Project description:The inhibitor-?B kinase-nuclear factor-?B (IKK-NF-?B) and epidermal growth factor receptor-activator protein-1 (EGFR-AP1) pathways are often co-activated and promote malignant behavior, but the underlying basis for this relationship is unclear. Resistance to inhibitors of IKK? or EGFR is observed in head and neck squamous cell carcinomas (HNSCC). Here, we reveal that both IKK? and ? contribute to nuclear activation of canonical and alternate NF-?B/REL family transcription factors, and overexpression of signal components that enhance co-activation of the EGFR-AP1 pathway. We observed that IKK? and IKK? exhibit increased protein expression, nuclear localization, and phosphorylation in HNSCC tissues and cell lines. Individually, IKK activity varied among different cell lines, but overexpression of both IKKs induced the strongest NF-?B activation. Conversely, siRNA knock down of both IKKs significantly decreased nuclear localization and phosphorylation of canonical RELA and I?B? and alternative p52 and RELB subunits. Knock down of both IKKs more effectively inhibited NF-?B activation, broadly modulated gene expression and suppressed cell proliferation and migration. Global expression profiling revealed that NF-?B, cytokine, inflammatory response and growth factor signaling are among the top pathways and networks regulated by IKKs. Importantly, IKK? and IKK? together promoted the expression and activity of transforming growth factor ?, EGFR and AP1 transcription factors cJun, JunB and Fra1. Knock down of AP1 subunits individually decreased 8/15 (53%) of IKK-targeted genes sampled and similarly inhibited cell proliferation and migration. Mutations of NF-?B and AP1-binding sites abolished or decreased IKK-induced interleukin-8 (IL-8) promoter activity. Compounds such as wedelactone with dual IKK inhibitory activity and geldanomycins that block IKK?/? and EGFR pathways were more active than IKK?-specific inhibitors in suppressing NF-?B activation and proliferation and inducing cell death. We conclude that IKK? and IKK? cooperatively activate NF-?B and EGFR/AP1 networks of signaling pathways and contribute to the malignant phenotype and the intrinsic or acquired therapeutic resistance of HNSCC.

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IKK? phosphorylates kindlin-2 to induce invadopodia formation and promote colorectal cancer metastasis.

Publications

IKKε phosphorylates kindlin-2 to induce invadopodia formation and promote colorectal cancer metastasis.

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