Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast
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Research Article Cell biology Oncology

Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis

Abstract

Current therapies to treat non–small cell lung carcinoma (NSCLC) have proven ineffective owing to transient, variable, and incomplete responses. Here we show that ABL kinases, ABL1 and ABL2, promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses NSCLC metastasis to brain and bone, and other organs. ABL kinases are required for expression of prometastasis genes. Notably, ABL1 and ABL2 depletion impairs extravasation of lung adenocarcinoma cells into the lung parenchyma. We found that ABL-mediated activation of the TAZ and β-catenin transcriptional coactivators is required for NSCLC metastasis. ABL kinases activate TAZ and β-catenin by decreasing their interaction with the β-TrCP ubiquitin ligase, leading to increased protein stability. High-level expression of ABL1, ABL2, and a subset of ABL-dependent TAZ- and β-catenin–target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature.

Authors

Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast

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Figure 8

Activated forms of β-catenin and TAZ rescue metastasis in lung cancer cells lacking ABL kinases.

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Activated forms of β-catenin and TAZ rescue metastasis in lung cancer ce...
(A) PC9 or PC9 cells expressing activated β-catenin (BC4SA) or activated TAZ (TAZ4SA) were transduced with lentiviruses encoding either scrambled (SCR) or ABL1/ABL2-specific (AA) shRNAs and cells were delivered by intracardiac injection into nude mice. Representative images are shown for indicated groups. (B) Bioluminescent imaging counts (in photons per second [p/s]) for each group are shown (SCR n = 16, AA n = 18, BC4SA-AA n = 8, TAZ4SA-AA n = 8). Data are represented as mean ± SEM; P values were calculated using 1-way ANOVA followed by Tukey’s honest significant difference test. *P < 0.05; NS, not significant. (C) Depletion of ABL1 and ABL2 and overexpression of TAZ4SA and BC4SA proteins was confirmed by Western blotting with the indicated antibodies. Activation of the β-catenin pathway was assessed by blotting for AXIN2. The same samples were run contemporaneously in several parallel gels to blot with indicated antibodies.