The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

Shih, Hung Ju; Chu, Kang Lin; Wu, Meng Hsun; Wu, Pei Hsuan; Chang, Wei‐Min; Chu, Jan Show; Wang, Lily; Takeuchi, Hideki; Ouchi, Toru; Hsu, Hsin Ling

doi:10.4161/cc.11.5.19452

Cited by 14 publications

(17 citation statements)

References 64 publications

(84 reference statements)

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“…30 The cells were further transfected with scrambled shRNA or pMKO.1 puro p53 shRNA 2 (Addgene) to deplete p53. Similarly, YY1 and EGFR were, respectively, inhibited in cells using SureSilencing YY1 shRNA (SABiosciences) and EGFR shRNA (SABiosciences) with a TransIT-LT1 transfection reagent (Mirus Bio LLC, Madison, WI, USA) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…21, 22, 23, 24 We have previously shown that enhanced MCT-1 activity decreases the promoter function, protein stability and activity of p53; therefore, overexpression of MCT-1 advances tumorigenicity in a p53-null background. 25, 26, 27 Multiple MCT-1 functions have been discovered that induce cell transformation and survival, 28, 29 cause catastrophic mitosis 25, 30, 31 and promote genomic instability. 25, 26 In the MCT-1 oncogenic pathway, we have demonstrated that the expression of Shc (Src homology 2 domain-containing transforming protein) proteins is increased, which stimulates extracellular-regulated kinase and Ras signaling.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

et al. 2017

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Tumor cells often produce high levels of reactive oxygen species (ROS) and display an increased ROS scavenging system. However, the molecular mechanism that balances antioxidative and oxidative stress in cancer cells is unclear. Here, we determined that oncogenic multiple copies in T-cell malignancy 1 (MCT-1) activity promotes the generation of intracellular ROS and mitochondrial superoxide. Overexpression of MCT-1 suppresses p53 accumulation but elevates the manganese-dependent superoxide dismutase (MnSOD) level via the YY1-EGFR signaling cascade, which protects cells against oxidative damage. Conversely, restricting ROS generation and/or targeting YY1 in lung cancer cells effectively inhibits the EGFR-MnSOD signaling pathway and cell invasiveness induced by MCT-1. Significantly, MCT-1 overexpression in lung cancer cells promotes tumor progression, necrosis and angiogenesis, and increases the number of tumor-promoting M2 macrophages and cancer-associated fibroblasts in the microenvironment. Clinical evidence further confirms that high expression of MCT-1 is associated with an increase in YY1, EGFR and MnSOD expression, accompanied by tumor recurrence, poor overall survival and EGFR mutation status in patients with lung cancers. Together, these data indicate that the MCT-1 oncogenic pathway is implicated in oxidative metabolism and lung carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

et al. 2017

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“…Abs recognizing p53 (EMD Millipore, Darmstadt, Germany), MnSOD (Enzo, Farmingdale, NY, USA), p21 (Santa Cruz, Dallas, Texas), p47 phox (Ab-345) (SAB, College Park, MD, USA), phospho-p47 phox (Ser345) (Elabscience, Houston, TX, USA), F4/80 and YY1 (GeneTex, Inc, Irvine, CA, USA), CD80 and CD163 (Abcam, Cambridge, MA, USA) were purchased as indicated. The SDS-PAGE and immunoblotting analysis was conducted as described previously [59].…”

Section: Antibodies (Abs)mentioning

confidence: 99%

Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression

Chen

Tseng

Chen

et al. 2020

Cancers

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Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.

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“…MCT-1 ( m ultiple c opies in T -cell malignancy 1) oncogene stimulates Ras and AKT signaling function. 26 , 27 , 28 Similar to PTEN, 14 MCT-1 relocates from the cytoplasm to the nucleus upon genotoxicity. 29 In support of MCT-1 oncogenic role in genomic instability, MCT-1 suppresses p53 activity and increases the frequency of massive chromosomal aberrations upon DNA damage.…”

Section: Introductionmentioning

confidence: 99%

“… 29 In support of MCT-1 oncogenic role in genomic instability, MCT-1 suppresses p53 activity and increases the frequency of massive chromosomal aberrations upon DNA damage. 27 , 29 Depletion of p53 enhances the MCT-1 oncogenic effect on chromosomal destabilization, mitotic abnormality and tumor growth, 27 , 28 , 30 implying an antagonism between p53 and MCT-1 in the neoplastic progression.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

et al. 2014

Oncogene

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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.

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The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

Cited by 14 publications

References 64 publications

Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression

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

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