Response to Rotenone Is Glucose-Sensitive in a Model of Human Acute Lymphoblastic Leukemia: Involvement of Oxidative Stress Mechanism, DJ-1, Parkin, and PINK-1 Proteins

Abstract EN

To establish the effect of low (11 mM) and high (55 mM) glucose concentrations (G11, G55) on Jurkat cells exposed to rotenone (ROT, a class 5 mitocan).

We demonstrated that ROT induces apoptosis in Jurkat cells cultured in G11 by oxidative stress (OS) mechanism involving the generation of anion superoxide radical ( O 2 ∙ - , 68%)/hydrogen peroxide (H2O2, 54%), activation of NF- κ B (32%), p53 (25%), c-Jun (17%) transcription factors, and caspase-3 (28%), apoptosis-inducing factor (AIF, 36%) nuclei translocation, c-Jun N-terminal kinase (JNK) activation, and loss of mitochondria transmembrane potential ( Δ Ψ m , 62%) leading to nuclei fragmentation (~10% and ~40% stage I-II fragmented nuclei, resp.).

ROT induces massive cytoplasmic aggregates of DJ-1 (93%), and upregulation of Parkin compared to untreated cells, but no effect on PINK-1 protein was observed.

Cell death marker detection and DJ-1 and Parkin expression were significantly reduced when cells were cultured in G55 plus ROT.

Remarkably, metformin sensitized Jurkat cells against ROT in G55.

Our results indicate that a high-glucose milieu promotes resistance against ROT/H2O2-induced apoptosis in Jurkat cells.

Our data suggest that combined therapy by using mitochondria-targeted damaging compounds and regulation of glucose (e.g., metformin) can efficiently terminate leukemia cells via apoptosis in hyperglycemic conditions.