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

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.

Cell-intrinsic and -extrinsic mechanisms promote cell-type-specific cytokinetic diversity

“…Indeed, we found that both a high cell-cell contact area and proper spindle orientation, two indicators of successful cell fate signaling from P2 to EMS, are highly correlated with successful cytokinesis in EMS ( Figures 7 and 8 ), and that depletion of Src SRC-1 specifically causes division failure in the EMS cell, but not the P2 cell. In support of cell-fate signaling in cytokinetic diversity, both Wnt and Src-family kinase signaling have been implicated in both positive and negative regulations of cytokinesis in other cell contexts ( De Santis Puzzonia et al, 2016 ; Fumoto et al, 2012 ; Kasahara et al, 2007 ; Soeda et al, 2013 ; Kamranvar et al, 2016 ; Avanzi et al, 2012 ; Sánchez-Bailón et al, 2012 ; Wu et al, 2014 ; Ikeuchi et al, 2016 ; Jungas et al, 2016 ; Kakae et al, 2017 ), and in human cancer cell lines Wnt5a, its receptor Frizzled Fz2 , as well as a mediator of Wnt signaling, Dishevelled Dvl2 , all localize to the midbody at the division plane ( Fumoto et al, 2012 ; Kikuchi et al, 2010 ). Thus, Wnt and/or Src cell fate signaling pathway components may themselves, or via their downstream targets, function to protect against cytokinesis failure in the absence of a robust actomyosin contractile ring.…”

p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

“…More recently, overexpression of p190B was correlated with MCT1 (multiple copies in T-cell malignancy-1) expression in breast cancer. In vitro, MCT1-Src-p190B interaction gave rise to neoplastic multinucleation of breast cancer cells [110] that was suggested to favor tumorigenicity. This involvement of p190B was also studied in nasopharyngeal carcinoma and lung cancer where, respectively, miR-744 and miR-486-5 expressions correlated with p190B expression resulting in tumor progression and dissemination [111,112].…”

“…Several p190B loss-of-function studies in vitro and in vivo confirmed oncogenic role of p190B (Table 2). Depletion of p190B inhibits cell migration, cell invasion, tumor progression, and metastatic dissemination in different cell lines of lung cancer [112], breast cancer [110,113], hepatocellular carcinoma [114], and nasopharyngeal carcinoma [111].…”

MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer

“…Density regulated protein and the MCT-1 heterodimer bind to the 40S ribosomal subunit and, with the recruitment of tRNA, cooperatively regulate noncanonical translation initiation [ 15 , 16 ]. Moreover, MCT-1 affects mitotic progression via interacting with γ-tubulin molecule and Src/p190B complex [ 17 , 18 ]. MCT-1 destabilizes p53 and PTEN in a ubiquitin-dependent proteasome pathway [ 18 , 19 ].…”

“…Moreover, MCT-1 affects mitotic progression via interacting with γ-tubulin molecule and Src/p190B complex [ 17 , 18 ]. MCT-1 destabilizes p53 and PTEN in a ubiquitin-dependent proteasome pathway [ 18 , 19 ]. Consequently, MCT-1 expression advances the p53-null or PTEN-null cancer cell progression and chromosomal/nuclear aberrations [ 17 , 18 , 20 , 21 ].…”