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Metabolic Reprograming Via Silencing of Mitochondrial VDAC1 Expression Encourages Differentiation of Cancer Cells.

08:00 EDT 18th May 2019 | BioPortfolio

Summary of "Metabolic Reprograming Via Silencing of Mitochondrial VDAC1 Expression Encourages Differentiation of Cancer Cells."

The mitochondrial gatekeeper voltage-dependent anion channel 1 (VDAC1) controls metabolic and energy cross-talk between mitochondria and the rest of the cell and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of downregulated VDAC1 expression in the U-87MG glioblastoma, MDA-MB-231 triple-negative breast cancer (TNBC), and A549 lung cancer cell lines, using small interfering RNA (siRNA) specific to human VDAC1 (si-hVDAC1). The cells were subjected to si-hVDAC1 (50 nM) treatment for 5-20 days. Although VDAC1 silencing occurred within a day, the cells underwent reprograming with respect to rewiring metabolism, elimination of cancer stem cells (CSCs), and alteration of transcription factor (TF) expression and proteins associated with differentiation, with maximal changes being observed after 3 weeks of silencing VDAC1 expression. The differentiation into fewer tumorigenic cells may be associated with the elimination of CSCs. These alterations are interconnected, as protein up- or downregulation occurred simultaneously, starting 15-20 days after VDAC1 levels were first decreased. Moreover, the VDAC1 depletion-mediated effects on a network of key regulators of cell metabolism, CSCs, TFs, and other factors leading to differentiation are coordinated and are common to the glioblastoma multiforme (GBM) and lung and breast cancer cell lines, despite differing in origin and carried mutations. Thus, our study showed that VDAC1 depletion triggers reprograming of malignant cancer cells into terminally differentiated cells and that this may be a promising therapeutic approach for various cancers.

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Journal Details

This article was published in the following journal.

Name: Molecular therapy. Nucleic acids
ISSN: 2162-2531
Pages: 24-37

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Medical and Biotech [MESH] Definitions

Interruption or suppression of the expression of a gene at transcriptional or translational levels.

A mitochondrial uncoupling protein that is expressed in many tissues and exhibits the greatest expression in SKELETAL MUSCLE. It regulates mitochondrial ATP production and the generation of REACTIVE OXYGEN SPECIES.

A transcriptional co-activator for NUCLEAR RECEPTORS. It is characterized by an N-terminal LxxLL sequence, a region that interacts with PPAR GAMMA, and a C-terminal RNA RECOGNITION MOTIF. It increases expression of MITOCHONDRIAL UNCOUPLING PROTEIN to regulate genes involved in metabolic reprogramming in response to dietary restriction and the integration of CIRCADIAN RHYTHMS with ENERGY METABOLISM.

A winged-helix transcription factor that regulates GENE expression in metabolic tissues. It plays a role in HOMEOSTASIS of GLUCOSE and controls expression of GLUT2 PROTEIN.

The artificial induction of GENE SILENCING by the use of RNA INTERFERENCE to reduce the expression of a specific gene. It includes the use of DOUBLE-STRANDED RNA, such as SMALL INTERFERING RNA and RNA containing HAIRPIN LOOP SEQUENCE, and ANTI-SENSE OLIGONUCLEOTIDES.

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