IKKε Phosphorylates Kindlin-2 to Induce Invadopodia Formation and Promote Colorectal Cancer Metastasis

Overview

Journal Theranostics

Date 2020 Feb 28

PMID 32104508

Citations 10

Authors

Ge Liu

Yantao Bao

Chaohua Liu

Qinchang Zhu

Lin Zhao

Xiaopeng Lu

Qian Zhu

Yafei Lv

Feng Bai

He Wen

Yujie Sun

Wei-Guo Zhu

Affiliations

Soon will be listed here.

Abstract

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. : 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 invasive capacity of CRC cells . Effects of IKKε knockdown or pharmacological inhibition on CRC metastasis were examined in mice. Immunohistochemistry staining was used to detect expression levels of IKKε in CRC patient tissues, and its association with prognosis in CRC patients was also analyzed. Immunoprecipitation, western blotting and kinase assay were constructed to investigate the molecular mechanisms. : IKKε 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 IKKε altered invadopodia formation and the migratory and invasive capacity of CRC cells . , knockdown or pharmacological inhibition of IKKε significantly suppressed metastasis of CRC cells in mice. IKKε knockdown also inhibited invadopodia formation . Clinical investigation of tumor specimens from 191 patients with CRC revealed that high IKKε expression correlates with metastasis and poor prognosis of CRC. Mechanistically, IKKε directly binds to and phosphorylates kindlin-2 at serine 159; this effect mediates the IKKε-induced invadopodia formation and promotion of CRC metastasis. : We identify IKKε as a novel regulator of invadopodia formation and a unique mechanism by which IKKε promotes the metastasis of CRC. Our study suggests that IKKε is a potential target to suppress CRC metastasis.

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