Triple-negative breast cancers (TNBCs) are characterized by poor survival, prognosis, and gradual resistance to cytotoxic chemotherapeutics, like doxorubicin (DOX). The clinical utility of DOX is limited by its cardiotoxic and chemoresistant effects that manifest over time. To induce chemoresistance, TNBC rewires oncogenic gene expression and cell signaling pathways. Recent studies have demonstrated that reprogramming of branched-chain amino acids (BCAAs) metabolism facilitates tumor growth and survival. Branched-chain ketoacid dehydrogenase kinase (BCKDK), a regulatory kinase of the rate-limiting enzyme of the BCAA catabolic pathway, is reported to activate RAS/RAF/MEK/ERK signaling to promote tumor cell proliferation. However, it remains unexplored if BCKDK action remodels TNBC proliferation and survival per se and influences susceptibility to DOX-induced genotoxic stress. TNBC cells treated with DOX exhibited reduced BCKDK expression and intracellular BCKAs. Genetic and pharmacological inhibition of BCKDK in TNBC cell lines also showed a similar reduction in intracellular and secreted BCKAs. BCKDK silencing in TNBC cells downregulated mitochondrial metabolism genes, reduced electron complex protein expression, oxygen consumption, and ATP production. Transcriptome analysis of BCKDK silenced cells confirmed dysregulation of mitochondrial metabolic networks and upregulation of the apoptotic signaling pathway. Furthermore, BCKDK inhibition with concurrent DOX treatment exacerbated apoptosis, caspase activity, and loss of TNBC proliferation. Inhibition of BCKDK in TNBC also upregulated sestrin 2 and concurrently decreased mTORC1 signaling and protein synthesis. Overall, loss of BCKDK action in TNBC remodels BCAA flux, reduces protein translation triggering cell death, ATP insufficiency, and susceptibility to genotoxic stress.
Whey peptides exacerbate body weight gain and perturb systemic glucose and tissue lipid metabolism in male high-fat fed mice. D’Souza K, Acquah C, Mercer A, Paudel Y, Pulinilkunnil T, Udenigwe CC, Kienesberger PC. Food Funct., 2021, Advance Article
Consumption of milk-derived whey proteins has been demonstrated to have insulin-sensitizing effects in mice and humans, in part through the generation of bioactive whey peptides. While whey peptides can prevent insulin resistance in vitro, it is unclear whether consumption of whey peptides can prevent obesity-induced metabolic dysfunction in vivo. We sought to determine whether whey peptides consumption can protect from high fat (HF) diet-induced obesity and dysregulation of glucose homeostasis. Male C57BL/6J mice were fed either a low or HF diet for 13 weeks. HF diet fed mice were provided drinking water with no addition (control), undigested whey protein isolate (WPI, 1 mg ml−1) or whey protein hydrolysate (WPH, 1 mg ml−1) throughout the diet regimen. Mice consuming WPH gained more body weight and were more glucose intolerant compared to those consuming WPI or water only. Despite increased body weight gain, perigonadal adipose tissue weight and lipid accumulation were unchanged. However, excess lipids accumulated ectopically in the liver and skeletal muscle in mice consuming WPH, which was associated with elevated inflammatory markers systemically and in adipose tissue, liver, and skeletal muscle. In skeletal muscle, mitochondrial fat oxidation and electron transport chain proteins were decreased with WPH consumption, indicative of mitochondrial dysfunction. Taken together, our results demonstrate that WPH, but not WPI, exacerbates HF-induced body weight gain and impairs glucose homeostasis, which is accompanied by increased inflammation, ectopic fat accumulation and mitochondrial dysfunction. Thus, our results argue against the use of dietary whey peptide supplementation as a preventative option against HF diet-induced metabolic dysfunction. Read here.
Disrupted branched-chain amino acid catabolism impair cardiac insulin signaling and is associated with adverse cardiometabolic outcomes. BISWAS D, PULINILKUNNIL T. J Mol Cell Cardiol . 2020 Dec 27;153:93-94. doi: 10.1016/j.yjmcc.2020.12.011.
Branched-chain amino acids (BCAAs), leucine (Leu), isoleucine (Ile) and valine (Val), account for ~20% of dietary protein intake . BCAAs are reversibly transaminated to their corresponding branched-chain keto acids (BCKAs) by branched-chain aminotransferase (BCAT). BCKAs are oxidatively decarboxylated by branched-chain ketoacid dehydrogenase (BCKDH). BCKDH activity is inhibited by branched-chain ketoacid dehydrogenase kinase (BCKDK) mediated inhibitory phosphorylation or activated by protein phosphatase 2C (PP2Cm) induced dephosphorylation Read here