MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation.

M-H Wu,Y-A Chen,K-W Chang,I-S Chang,H-L Hsu,H-H Chen,L-H Wang

doi:10.1038/onc.2014.125

Abstract

Multinucleation is associated with malignant neoplasms; however, the molecular mechanism underlying the nuclear abnormality remains unclear. Loss or mutation of PTEN promotes the development of malignant tumors. We now demonstrate that increased expression of the oncogene MCT-1 (multiple copies in T-cell malignancy 1) antagonizes PTEN gene presentation, PTEN protein stability and PTEN functional activity, thereby further promoting phosphoinositide 3 kinase/AKT signaling, survival rate and malignancies of the PTEN-deficient cells. In the PTEN-null cancer cells, MCT-1 interacts with p190B and Src in vivo, supporting that they are in proximity of the signaling complexes. MCT-1 overexpression and PTEN loss synergistically augments the Src/p190B signaling function that leads to inhibition of RhoA activity. Under such a condition, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure is enhanced, driving an Src/p190B/RhoA-dependent neoplastic multinucleation. Targeting MCT-1 by the short hairpin RNA markedly represses the Src/p190B function, improves nuclear structures and suppresses xenograft tumorigenicity of the PTEN-null breast cancer cells. Consistent with the oncogenic effects in vitro, clinical evidence has confirmed that MCT-1 gene stimulation is correlated with p190B gene promotion and PTEN gene suppression in human breast cancer. Accordingly, MCT-1 gene induction is recognized as a potential biomarker of breast tumor development. Abrogating MCT-1 function may be a promising stratagem for management of breast cancer involving Src hyperactivation and/or PTEN dysfunction.

Highlights

Loss-of-function mutations in the catalytic domain of PTEN or the reduced PTEN expression through loss of heterozygosity has been identified in human cancers and inherited cancer-predisposition syndromes.[1,2,3,4,5] PTEN inhibits phosphoinositide 3 kinase (PI3K)/AKT signaling pathway.[6]
We identified a novel inhibitor of PTEN and the interacting protein of Src/p190B, MCT-1, and demonstrated that PTEN loss and MCT-1 induction synergistically promoted the acytokinetic division and neoplastic multinucleation via the Src/ p190B signaling activation
The epidermal growth factor (EGF)-induced AKT phosphorylation was markedly suppressed by LY and attenuated by an Src inhibitor (PP2) in the MCT-1-expressing MCF-10A cells (Supplementary Figure S1c, lanes 9 and 10), showing the involvement of Src and PI3K in the MCT-1 pathway

Summary

Introduction

Loss-of-function mutations in the catalytic domain of PTEN or the reduced PTEN expression through loss of heterozygosity has been identified in human cancers and inherited cancer-predisposition syndromes.[1,2,3,4,5] PTEN inhibits phosphoinositide 3 kinase (PI3K)/AKT signaling pathway.[6] A subtle decrease in PTEN amount (80% of normal levels) induces tumorigenicity, in breast cancer.[7] PTEN gene is methylated in ductal carcinoma in situ and in early invasive breast cancer, indicating the epigenetic inactivation of PTEN during cancer progression.[8] NEDD4-1 catalyzes PTEN polyubiquitination and degradation decreasing the cytoplasmic PTEN in carcinogenesis.[9] PTEN monoubiquitination enhances its nuclear import and antitumor effect perhaps by preventing nuclear AKT activity and genomic instability.[10,11]

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Conclusion