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Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept.

ABSTRACT: Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the "disappearance" of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks.

SUBMITTER: Arif T

PROVIDER: S-EPMC6912264 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept.

Arif Tasleem T Stern Oriel O Pittala Srinivas S Chalifa-Caspi Vered V Shoshan-Barmatz Varda V

Cells 20191028 11

Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprogrami ...[more]

PMID: 31661894

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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:Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial-mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism-epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.

Project description:BackgroundMitochondrial metabolism has been proposed as an attractive target for breast cancer therapy. The discovery of new mechanisms underlying mitochondrial dysfunction will facilitate the development of new metabolic inhibitors to improve the clinical treatment of breast cancer patients. DYNLT1 (Dynein Light Chain Tctex-Type 1) is a key component of the motor complex that transports cellular cargo along microtubules in the cell, but whether and how DYNLT1 affects mitochondrial metabolism and breast cancer has not been reported.MethodsThe expression levels of DYNLT1 were analyzed in clinical samples and a panel of cell lines. The role of DYNLT1 in breast cancer development was investigated using in vivo mouse models and in vitro cell assays, including CCK-8, plate cloning and transwell assay. The role of DYNLT1 in regulating mitochondrial metabolism in breast cancer development is examined by measuring mitochondrial membrane potential and ATP levels. To investigate the underlying molecular mechanism, many methods, including but not limited to Co-IP and ubiquitination assay were used.ResultsFirst, we found that DYNLT1 was upregulated in breast tumors, especially in ER + and TNBC subtypes. DYNLT1 promotes the proliferation, migration, invasion and mitochondrial metabolism in breast cancer cells in vitro and breast tumor development in vivo. DYNLT1 colocalizes with voltage-dependent anion channel 1 (VDAC1) on mitochondria to regulate key metabolic and energy functions. Mechanistically, DYNLT1 stabilizes the voltage-dependent anion channel 1 (VDAC1) by hindering E3 ligase Parkin-mediated VDAC1 ubiquitination and degradation.ConclusionOur data demonstrate that DYNLT1 promotes mitochondrial metabolism to fuel breast cancer development by inhibiting Parkin-mediated ubiquitination degradation of VDAC1. This study suggests that mitochondrial metabolism can be exploited by targeting the DYNLT1-Parkin-VDAC1 axis to improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC).

Dataset Information

Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept.

Publications

Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept.

Similar Datasets

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