Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH‐WT gliomas

Conway, Myra E.; Hull, Jonathon; Hindy, Maya El; Taylor, Scott; Amraoui, Farah El; Paton-Thomas, C.; White, Paul; Williams, Maggie; Ellis, Hayley Patricia; Bertoni, Anna; Radlwimmer, Bernhard; Hutson, Susan M.; Kurian, Kathreena M.

doi:10.1111/bpa.12385

Cited by 8 publications

(11 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Branched-chain amino acids (BCAA) catabolism is abnormal in many human diseases (Burrage et al, 2014, Sonnet et al, 2016, Watanabe et al, 1984). Branched-chain amino transferase (BCAT) is the first enzyme in BCAA catabolism which has a higher activity in tumors and has been shown to be a useful marker for grading and genetic characterization in glioma, colorectal cancer (CRC) and medulloblastoma (Conway et al, 2016, de Bont et al, 2008, Mitchell et al, 2014). However, healthy human prostate tissue was found to have elevated BCAT levels relative to malignant tissue (Billingsley et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

et al. 2017

View full text Add to dashboard Cite

Branched-chain amino acids catabolism plays an important role in human cancers. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and the new global incidence is over 1.2 million cases. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a rate-limiting enzyme in branched-chain amino acids catabolism, which plays an important role in many serious human diseases. Here we investigated that abnormal branched-chain amino acids catabolism in colorectal cancer is a result of the disease process, with no role in disease initiation; BCKDK is widely expressed in colorectal cancer patients, and those patients that express higher levels of BCKDK have shorter survival times than those with lower levels; BCKDK promotes cell transformation or colorectal cancer ex vivo or in vivo. Mechanistically, BCKDK promotes colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation, rather than by branched-chain amino acids catabolism. And the process above could be inhibited by a BCKDK inhibitor, phenyl butyrate.

show abstract

Section: Introductionmentioning

confidence: 99%

BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…25 While this was the first study to use an animal model of BCATm in cancer, other studies using siRNA to silence BCATm, or comparing the expression of BCATm in healthy and cancer tissues, also suggested that a loss of BCATm leads to suppression of tumour growth, while BCATm overexpression has the opposite effect. 23,24,39 In this study, however, the diet composition significantly impacted the ability of BCATmKO mice to repress cancer. As previously reported, BCATmKO mice are maintained on a choice BCAA diet to escape the deleterious effects of toxic BCAA accumulation.…”

Section: Discussionmentioning

confidence: 53%

“…Heart hypertrophy was previously linked with the well-established role of BCAAs, and particularly leucine, in the regulation of mTORC1 signalling. 23,24,39 In fact, feeding BCATmKO mice with a diet supplemented with rapamycin prevented the heart enlargement of BCATmKO animals, suggesting that mTORC1 is the mediator of these effects. 35…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma

et al. 2018

Self Cite

View full text Add to dashboard Cite

Background The mitochondrial branched-chain aminotransferase (BCATm) is a recently discovered cancer marker with a poorly defined role in tumour progression. Methods To understand how a loss of function of BCATm affects cancer, the global knockout mouse BCATmKO was challenged with EL-4 lymphoma under different diet compositions with varying amounts of branched-chain amino acids (BCAAs). Next, the growth and metabolism of EL-4 cells were studied in the presence of different leucine concentrations in the growth medium. Results BCATmKO mice experienced delayed tumour growth when fed standard rodent chow or a normal BCAA diet. Tumour suppression correlated with 37.6- and 18.9-fold increases in plasma and tumour BCAAs, 37.5% and 30.4% decreases in tumour glutamine and alanine, and a 3.5-fold increase in the phosphorylation of tumour AMPK in BCATmKO mice on standard rodent chow. Similar results were obtained with a normal but not with a choice BCAA diet. Conclusions Global deletion of BCATm caused a dramatic build-up of BCAAs, which could not be utilised for energy or amino acid synthesis, ultimately delaying the growth of lymphoma tumours. Furthermore, physiological, but not high, leucine concentrations promoted the growth of EL-4 cells. BCATm and BCAA metabolism were identified as attractive targets for anti-lymphoma therapy.

show abstract

“…The hBCAT proteins exist in two main isoforms, the mitochondrial hBCAT isoform (hBCATm protein, BCAT2 gene) is widely expressed in most tissues, whereas the cytosolic hBCAT (hBCATc protein, BCAT1 gene) is restricted to highly specialised tissues including brain and placenta [16]. Increased levels of the BCAT gene, BCAT1 have been extensively reported in malignancies including gliomas [17,18], ovarian [19], colorectal [20], gastric cancer [21], nasopharyngeal carcinomas [22], breast cancer [23] and chronic myeloid leukemia (CML) [24]. In gliomas, increased hBCATc and hBCATm expression has been limited to gliomas with wild-type isocitrate dehydrogenase 1 (IDH1), cytosolic and IDH2, mitochondrial [17,18].…”

Section: Introductionmentioning

confidence: 99%

Differential expression of the BCAT isoforms between breast cancer subtypes

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH‐WT gliomas

Cited by 8 publications

References 7 publications

BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma

Differential expression of the BCAT isoforms between breast cancer subtypes

Contact Info

Product

Resources

About