t-Darpp Activates IGF-1R Signaling to Regulate Glucose Metabolism in Trastuzumab-Resistant Breast Cancer Cells

Lenz, Gal; Hamilton, Angelica; Geng, Shuhui; Hong, Teresa; Kalkum, Markus; Momand, Jamil; Kane, Susan E.; Huss, Janice M.

doi:10.1158/1078-0432.ccr-17-0824

Cited by 40 publications

(41 citation statements)

References 47 publications

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“…Several studies have demonstrated that DARPP-32 and t-DARPP protect cancer cells from drug-induced apoptosis, which is dependent upon their T75 phosphorylation residue 9 , 10 and involves upregulation of Akt and Bcl2 proteins 16 , 18 , 19 . Most recently, t-DARPP overexpression was shown to promote activation of insulin-like growth factor-1 receptor signaling to regulate glucose metabolism as a mechanism of trastuzumab resistance in breast cancer cells 20 . To date, the role of DARPP-32 isoforms in lung cancer remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration

et al. 2018

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Lung cancer is the leading cause of cancer-related death worldwide. Here we demonstrate that elevated expression of dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant t-DARPP promote lung tumor growth, while abrogation of DARPP-32 expression in human non-small-cell lung cancer (NSCLC) cells reduces tumor growth in orthotopic mouse models. We observe a physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NF-κB2) signaling. Bioinformatics analysis of 513 lung adenocarcinoma patients reveals that elevated t-DARPP isoform expression is associated with poor overall survival. Histopathological investigation of 62 human lung adenocarcinoma tissues also shows that t-DARPP expression is elevated with increasing tumor (T) stage. Our data suggest that DARPP-32 isoforms serve as a negative prognostic marker associated with increasing stages of NSCLC and may represent a novel therapeutic target.

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Section: Introductionmentioning

confidence: 99%

DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration

et al. 2018

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“…To meet with the need of rapid cell growth, the key regulators of glycolysis, such as glucose transporters (GLUTs) and glycolytic enzymes, are usually overexpressed in cancer cells. It has been documented that insulin stimulated glucose metabolism via insulin growth factor receptor (IGF-1R), consequently activating the phosphorylation of AKT and up-regulated the expression of GLUTs [22][23][24]. IGF-1R and AKT-GLUT1 axis might be promising targets of miRNAs to affect the progression of cancers.…”

Section: Introductionmentioning

confidence: 99%

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most common cancers globally. An increasing body of evidence has demonstrated the critical function of microRNAs (miRNAs) in the initiation and progression of human cancers. Here, we showed that miR-505 was down-regulated in HCC tissues and cell lines. Reduced expression of miR-505 was significantly correlated with the worse prognosis of HCC patients. Overexpression of miR-505 suppressed the proliferation, colony formation and induced apoptosis of both HepG2 and Huh7 cells. Further mechanism study uncovered that miR-505 bound the 3′-untranslated region (3′-UTR) of the insulin growth factor receptor (IGF-1R) and inhibited the expression of IGF-1R in HCC cells. The down-regulation of IGF-1R by miR-505 further suppressed the phosphorylation of AKT at the amino acid S473. Consistently, the abundance of glucose transporter (GLUT) 1 (GLUT1) was reduced with the overexpression of miR-505. Down-regulation of GLUT1 by miR-505 consequently attenuated the glucose uptake, lactate production and ATP generation of HCC cells. Collectively, our results demonstrated the tumor suppressive function of miR-505 possibly via inhibiting the glycolysis of HCC cells. These findings suggested miR-505 as an interesting target for designing anti-cancer strategy in HCC.

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“…Co-targeting of the IGF-IR and EGFR axes may therefore provide an efficacious therapeutic strategy for GBM (24). It may also be relevant to brain metastases originating from other malignancies, such as breast cancer (60).…”

Section: Discussionmentioning

confidence: 99%

Glioma Cells With Genetically Engineered IGF-I Receptor Downregulation Can Persist in the Brain in a Dormant State

2020

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Glioblastoma multiforme is an aggressive malignancy, resistant to standard treatment modalities and associated with poor prognosis. We analyzed the role of the IGF system in intracerebral glioma growth using human and rat glioma cells. The glioma cells C6 and U87MG were transduced with a genetically engineered retrovirus expressing type 1 insulin-like growth factor (IGF-IR) antisense RNA, either before or after intra-cerebral implantation of the cells into Sprague Dawley rats or nude mice, respectively and tumor growth and animal survival were monitored. Rat glioma cells transduced prior to orthotopic, intra-cerebral implantation had a significantly increased apoptotic rate in vivo and a significantly reduced tumor volume as seen 24 days post implantation (p < 0.0015). This resulted in increased survival, as greater than 70% of the rats were still alive 182 days after tumor implantation (p < 0.01), as compared to 80% mortality by day 24 in the control group. Histomorphology and histochemical studies performed on brain tissue that was obtained from rats that survived for 182 days revealed numerous single cells that were widely disseminated throughout the brain. These cells expressed the β-galactosidase marker protein, but were Ki67negative, suggesting that they acquired a dormant phenotype. Direct targeting of the C6 cells with retroviral particles in vivo was effective and reduced tumor volumes by 22% relative to controls. A significant effect on tumor growth was also seen with human glioma U87MG cells that were virally transduced and implanted intra-cerebrally in nude mice. We observed in these mice a significant reduction in tumor volumes and 70% of the animals were still alive 6 months after tumor implantation, as compared to 100% mortality in the control group by day 63. Our results show that IGF-IR targeting can inhibit the intracerebral growth of glioma cells. They also suggest that IGF-IR expression levels may determine a delicate balance between glioma cell growth, death and the acquisition of a dormant state in the brain.

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t-Darpp Activates IGF-1R Signaling to Regulate Glucose Metabolism in Trastuzumab-Resistant Breast Cancer Cells

Cited by 40 publications

References 47 publications

DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration

DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

Glioma Cells With Genetically Engineered IGF-I Receptor Downregulation Can Persist in the Brain in a Dormant State

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