Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo

Koren, Inbar; Raviv, Ziv; Shoshan‐Barmatz, Varda

doi:10.4161/cbt.9.12.11879

Cited by 61 publications

(65 citation statements)

References 38 publications

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“…In cancer cells, VDAC channels are significantly upregulated. As expected, downregulation of VDAC directly affects proliferation [84,85]. HK expression is also linked with VDAC quantities; in tumor cells, overexpression of HK-I and -II induces VDAC closure and prevents MPTP opening [86].…”

Section: +supporting

confidence: 57%

Disrupting cancer cell function by targeting mitochondria

Yan¹

2014

Integr Cancer Sci Therap

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Although each cancer type is individually distinct, most cancers initially occur due to genomic mutations of oncogenes and tumor suppressor genes, leading to enhancement or disruption of specific cellular processes, including mitochondrial-mediated events. As an organelle necessary for both cell survival and cell death, the mitochondrion is involved in a variety of diseases, including cancer. Specific alterations to mitochondrial DNA in cancer can result in increased proliferation and avoidance of cell death pathways. Since cancer cells utilize mitochondria to enhance disease progression, specific targeting of mitochondrial-regulated processes and pathways may present advantageous anticancer treatments.

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Section: +supporting

confidence: 57%

Disrupting cancer cell function by targeting mitochondria

Yan¹

2014

Integr Cancer Sci Therap

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“…Tumors highly overexpress VDAC, promoting hexokinase interaction and stimulation of cancer cell glycolysis (Mathupala & Pedersen 2010). Downregulation of the expression of VDAC1 inhibits tumor cell growth both in vitro and in animal models (Koren et al 2010), thus representing a novel potential anti-cancer target in tumor (Mathupala & Pedersen 2010). VDAC1 also stabilizes StAR at the mitochondrial outer membrane, enabling the transport of cholesterol to the inner membrane to be converted to pregnenolone (Bose et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells

Poli¹,

Guasti²,

Rapizzi³

et al. 2013

Endocrine-Related Cancer

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At present, mitotane (MTT) represents the first-line pharmacological approach for the treatment of advanced adrenocortical carcinoma (ACC). Despite clear evidence that the drug can reduce the clinical signs of steroid excess in secreting ACC, the mechanism mediating the possible toxic effect of MTT on tumor cells still remains obscure. This study investigated the intracellular events underlying the toxic effect of MTT by studying qualitative and quantitative alterations in mitochondrial morphology and functions in human adrenocortical cancer cell lines, H295R and SW13. Increasing concentrations of MTT resulted in rapid intracellular accumulation and conversion of the drug. Cytostatic and cytotoxic effects were evident at doses corresponding to the therapeutic window (30-50 mM) through an apoptotic mechanism involving caspase 3/7. Electron microscopic analysis of cell mitochondria displayed MTT-induced dose-and time-dependent alterations in the morphology of the organelle. These alterations were characterized by a marked swelling and a decrease in the number of respiratory cristae, accompanied by a significant depolarization of the mitochondrial membrane potential, finally leading to the disruption of the organelle. A drastic reduction of oxygen consumption was observed due to mitochondrial membrane damage, which was accompanied by a decrease in the levels of VDAC1 integral membrane channel. These findings contribute to better understand the intracellular mechanism of action of MTT in ACC cells, showing that its cytotoxic effect seems to be mainly mediated by an apoptotic process activated by the disruption of mitochondria.

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“…Indeed, the importance of VDAC1 for cancer cells is further reflected in the finding that silencing VDAC1 expression reduced cellular ATP levels and cell growth [60]. Furthermore, when HeLa cervical cancer cells stably expressing shRNA directed against hVDAC1 were injected into nude mice, the development of a solid tumor was inhibited [420]. It has also been shown that VDAC1 silencing potentiated H 2 O 2 -induced apoptosis and impaired mitochondrial Ca 2+ loading, while silencing VDAC2 had the opposite effects [261].…”

Section: Vdac1-depletion Using Rnaimentioning

confidence: 99%

“…This dual function of VDAC1 in both cell metabolism and apoptosis, as mediated by the protein alone and regulated by associated polypeptides, points to VDAC1 as being a rational target for the development of a new generation of therapeutics. Such strategies include interference RNA to down-regulate VDAC1 expression levels [420], VDAC1-based peptides [155,197,288,290] and small molecules, such as methyl jesmonate [291]. Altogether, VDAC1-based strategies as anti-cancer therapies are expected to be highly effective, even in drug-resistance tumors, and will enhance the sensitivity of cancer cells toward chemotherapies, thereby reducing their side effects.…”

Section: Perspectivesmentioning

confidence: 99%

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Shoshan‐Barmatz

Ben-Hail

Admoni

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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214

254

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VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites, ions, nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of cancer cells. Indeed, this protein is over-expressed in many cancer types, and silencing of VDAC1 expression induces an inhibition of tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both cancer development and therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA able to impair energy and metabolic homeostasis, leading to arrested cancer cell growth and tumor development, as well VDAC1-based peptides that interact with anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of cancer cell to chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target. This article is part of a Special ...

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Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo

Cited by 61 publications

References 38 publications

Disrupting cancer cell function by targeting mitochondria

Disrupting cancer cell function by targeting mitochondria

Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells

The mitochondrial voltage-dependent anion channel 1 in tumor cells

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