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

ABSTRACT: 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.

SUBMITTER: Arif T

PROVIDER: S-EPMC6562189 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Arif Tasleem T Amsalem Zohar Z Shoshan-Barmatz Varda V

Molecular therapy. Nucleic acids 20190518

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 n ...[more]

PMID: 31195298

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Project description:Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual "tumour" showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target.

Project description:The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor-host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in cancerous cells and its effect on the TME. A major limitation in the study of tumor-host interactions is the difficulty in separating cancerous from non-cancerous signaling pathways within a tumor. Our strategy involved specifically silencing the expression of VDAC1 in the mitochondria of human-derived A549 lung cancer xenografts in mice, but not in the mouse-derived cells of the TME. Next-generation sequencing (NGS) analysis allows distinguishing the human or mouse origin of genes, thus enabling the separation of the bidirectional cross-talk between the TME and malignant cells. We demonstrate that depleting VDAC1 in cancer cells led to metabolic reprogramming, tumor regression, and the disruption of tumor-host interactions. This was reflected in the altered expression of a battery of genes associated with TME, including those involved in extracellular matrix organization and structure, matrix-related peptidases, angiogenesis, intercellular interacting proteins, integrins, and growth factors associated with stromal activities. We show that metabolic rewiring upon mitochondrial VDAC1 silencing in cancer cells affected several components of the TME, such as structural protein matrix metalloproteinases and Lox, and elicited a stromal response resembling the reaction to a foreign body in wound healing. As tumor progression requires a cooperative interplay between the host and cancer cells, and the ECM is intensively remodeled during cancer progression, VDAC1 depletion induced metabolic reprogramming that targeted both tumor cells and resulted in the alteration of the whole spectrum of TME-related genes, affecting the reciprocal feedback between ECM molecules, host cells, and cancer cells. Thus, VDAC1 depletion using si-VDAC1 represents therapeutic potential, inhibiting cancer cell proliferation and also inducing the modulation of TME components, which influences cancer progression, migration, and invasion.

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

Publications

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

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