BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer

Shafei, Mai Ahmed; Forshaw, Tom E.; Davis, Jasmine; Flemban, Arwa; Qualtrough, David; Dean, Sarah J.; Perks, Claire M; Dong, Ming; Newman, Robert H.; Conway, Myra E.

doi:10.18632/oncotarget.27607

Cited by 12 publications

(11 citation statements)

References 62 publications

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“…For instance, activated Akt was found to be the mediator in CD40-induced vascular endothelial growth factor (VEGF) production, a well-known protein that is upregulated in tumor cells [ 41 ]. Meanwhile, downstream signaling of PKC involves the direct activation of the RAF/MEK/Erk signaling pathway, in which the hyperactivation of this pathway is also associated with many human cancers [ 42 ]. Additionally, through the activation of mTORC1, BCAAs were found to reduce the expression of transforming growth factor beta 1 (TGF-β1) cytokines in both hepatic stellate cells and mouse hepatocytes [ 43 ].…”

Section: Circulation Of Bcaasmentioning

confidence: 99%

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases

Felicianna

et al. 2022

Biomedicines

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Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs’ distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs’ possible contribution to liver health.

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Section: Circulation Of Bcaasmentioning

confidence: 99%

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases

Felicianna

et al. 2022

Biomedicines

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“…Antitumor activity of trastuzumab was enhanced when combined with brusatol in HER2-positive breast cancer cells, which was attributed to the inhibition of the Nrf2/HO-1 and HER2-Akt/Erk1/2 signaling cascades [ 32 ]. Cytosolic branched-chain aminotransferase enhances the growth, migration along with the infiltration of triple-negative breast cancer cells through the IGF-1/insulin PI3K/Akt cascade, culminating in the up-regulation of FOXO3a and Nrf2, indicating a novel therapeutic target for breast cancer treatment [ 33 ]. These data suggest that the hypoxic/VEGF-A-Rap1b/VEGFR2 cascade facilitates nuclear translocation of Nrf2, Erk, and Akt signal pathways participate in Nrf2’s nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

Abnormal phenotype of Nrf2 is associated with poor prognosis through hypoxic/VEGF-A-Rap1b/VEGFR2 pathway in gastric cancer

Yang

Wang

Zhang

et al. 2022

Aging

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Metastasis is the major cause of death in gastric cancer patients and altered expression of Nrf2 is associated with cancer development. This study assessed Nrf2 and HO-1 expression and hypoxia-induced Nrf2 expression in the promotion of metastatic potential of gastric cancer cells, the relationship of Rap1b and Nrf2 was also discussed. Nrf2 and HO-1 expression were significantly associated with clinicopathological characteristic and were independent prognostic predictors in gastric cancer patients. Hypoxia up-regulated the expression of Nrf2, HO-1 and HIF-1α, whereas knockdown of Nrf2 inhibited cell invasion capacity and reduced the expression of Nrf2, HO-1 and HIF-1α. Patients in the Rap1b (+) Nrf2 (+) group had worst overall survival compared with those from other groups. Knockdown of Rap1b and Nrf2 significantly inhibited cell invasion capacity in the common group compared with the other groups. Hypoxia or VEGF-A facilitated the nuclear translocation of Nrf2 through Rap1b or VEGFR2. Hypoxia or VEGF-A did not induce the phosphorylation of P-Erk1/2 and P-Akt after knockdown of Rap1b or VEGFR2. Hypoxia promoted the gastric cancer malignant behavior through the upregulation of Rap1b and Nrf2. Hypoxia/VEGF-A-Rap1b/VEGFR2 facilitated the nuclear translocation of Nrf2. Targeting Rap1b and Nrf2 may be a novel therapeutic strategy for gastric cancer.

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“…In addition to metabolite regulation, ligand binding to HER2 can activate the PI3K/Akt pathway, where a role for activated Akt in tumorigenesis is widely recognised. As discussed, we have evidenced that BCATc regulates cell proliferation and migration through activation of the PI3K/Akt pathway, whilst suppressing Ras/ERK activation, highlighting the plasticity of tumours to advance and adapt to changing environments [ 26 ], in particular in response to HER2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…GSH plays an important role in redox homeostasis and tumour cell survival by protecting cells from damage caused by the reactive oxygen species (ROS) generated during oxidative stress [ 57 ]. Moreover, expression levels of hBCAT have been demonstrated to regulate the expression of nuclear factor (erythroid-derived 2)-like-2 (Nrf2), which is the primary transcription factor responsible for the regulation of genes encoding oxidative stress‐related proteins [ 26 ]. Hence, increased expression of hBCATm in the luminal A subtype is suggested to reduce ROS levels, thereby providing a mechanistic positive feedback loop which enhances SREBP1-induced IDH1 and hBCATm upregulation.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, perturbations in BCAA metabolism have also been a subject of increased interest [ 25 ] where upregulation of hBCATc has been reported to increase cell proliferation and migration in ER-negative breast cancer cells [ 23 ]. Our recent study showed that hBCATc regulates TNBC cell proliferation migration and invasion through the IGF-1/insulin PI3K/Akt pathway, culminating in the upregulation of FOXO3a and Nrf2, pointing to a novel therapeutic target for breast cancer treatment [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of the BCAT isoforms between breast cancer subtypes

et al. 2020

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Background Biological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated. Methods Using immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined. Results We show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression. Conclusion The cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism.

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BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer

Cited by 12 publications

References 62 publications

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases

Abnormal phenotype of Nrf2 is associated with poor prognosis through hypoxic/VEGF-A-Rap1b/VEGFR2 pathway in gastric cancer

Differential expression of the BCAT isoforms between breast cancer subtypes

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