Pan-Cancer Analysis of Voltage-Dependent Anion Channel (VDAC1) as a Cancer Therapeutic Target or Diagnostic Biomarker

Wang, Zhitong; Cheng, Yinchu; Song, Zaiwei; Zhao, Runhuai

doi:10.1155/2022/5946110

Cited by 9 publications

(10 citation statements)

References 46 publications

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“…VDAC1 overexpression, its oligomerization and apoptosis induction have been implicated in different diseases [37]. In cancers, VDAC1 is overexpressed [38][39][40], while its oligomerization and, thereby, apoptosis are prevented by the overexpression of anti-apoptotic proteins such as hexokinase and Bcl2, and their detachment from VDAC1 leads to VDAC1 oligomerization and apoptosis [22,37,39].…”

Section: Introductionmentioning

confidence: 99%

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Verma

Shteinfer‐Kuzmine

Kamenetsky

et al. 2022

Transl Neurodegener

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Background Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction. Methods To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests. Results In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load. Conclusions The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.

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Section: Introductionmentioning

confidence: 99%

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Verma

Shteinfer‐Kuzmine

Kamenetsky

et al. 2022

Transl Neurodegener

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“…Given that (1) NADH crosses the outer mitochondrial membrane through VDAC1 (Shoshan-Barmatz et al, 2010), (2) VDAC1 is overexpressed in many tumor cells lines(Wang et al, 2022) including iCCA and SKBR3 (Fig. S3) and (3) the SC18 molecule targeting the VDAC1 NADH binding site(Heslop et al, 2022) reduces mitochondrial NADH, we hypothesized that VA molecules can similarly impact mitochondrial energy generation by blocking the NADH transport.…”

Section: Resultsmentioning

confidence: 99%

VDAC1 selective molecules promote patients’-derived cancer organoids death through mitochondrial-dependent metabolic interference

Conti Nibali,

De Siervi,

Luchinat

et al. 2023

Preprint

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In the continuous pursuit of advanced cancer therapeutics, our research unveils the potential to selectively target Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1), a pivotal component in cellular metabolism and apoptosis. VDAC1’s role in metabolic rewiring and its subsequent prominence in many cancer types offer a unique intervention point. The incorporation of a systematic,in silicotoin vitromethodology identified novel VA (VDAC-Antagonist) molecules with the capability to selectively bind to VDAC1, displaying a substantial specificity towards cancer cells while sparing healthy ones.This research first led to the revelation of a specialized VDAC1 pocket, which accommodates the binding of these VA molecules, thereby instigating a selective displacement of NADH. The coenzyme is a critical metabolic substrate, and its displacement ensues in notable mitochondrial distress and a reduction in cell proliferation, specifically in cancer cells. Furthermore, meticulous analysis using organoids derived from intrahepatic cholangiocarcinoma patients (iCCA) demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules, correlating with the findings from commercial cell lines.Interestingly, VA molecules significantly reduced cell viability and demonstrated a lower impact on healthy cells than conventional treatments like gemcitabine. This differential impact is possibly due to the elevated expression of VDAC1 in various cancer cell lines, rendering them more susceptible to metabolic disruptions induced by VA molecules.This endeavor uncovers a multifaceted approach to cancer treatment, involving meticulous targeting of metabolic gatekeepers like VDAC1 using novel entities, thereby paving the way for developing more selective and refined cancer therapeutics. The identified VA molecules, albeit in the nascent stages, represent promising candidates for further optimization and development, potentially revolutionizing treatment modalities in cancer therapy through precise metabolic interventions.

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“…The expression of VDAC1 in squamous cell carcinoma cases presents an additional problem. The most recent (2022) and detailed report of Wang et al on VDAC1 “pan-cancer” activity presented an extensive list of tumor tissues in which VDAC1 was upregulated [ 42 ]. This list included “bladder urothelial carcinoma, breast invasive carcinoma, cholangiocarcinoma, colon adenocarcinoma, esophageal carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, prostate adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma”.…”

Section: Discussionmentioning

confidence: 99%

“…Approaching this topic from a survival prognosis viewpoint, overexpression of VDAC1 is related to the poor overall survival of adrenocortical carcinoma, breast invasive carcinoma, cervical and endocervical cancers, glioblastoma multiforme, lung adenocarcinoma, pancreatic adenocarcinoma, and skin cutaneous melanoma cases, and low VDAC1 expression is associated with a poor overall survival prognosis of kidney renal clear cell carcinoma cases [ 42 ]. No VDAC1-related survival prognosis reports for cases of esophageal carcinoma and lung squamous cell carcinoma were published to date.…”

Section: Discussionmentioning

confidence: 99%

Voltage-Dependent Anion Channel 1 Expression in Oral Malignant and Premalignant Lesions

et al. 2023

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Background: The voltage-dependent anion channel 1 protein (VDAC1) plays a role in cellular metabolism and survival. It was found to be down or upregulated (overexpressed) in different malignancies but it was never studied in application to oral lesions. The purpose of this study was to retrospectively evaluate the expression of VDAC1 in biopsies of oral premalignant, malignant, and malignancy-neutral lesions and to examine the possible correlations to their clinicopathological parameters. Materials and methods: 103 biopsies including 49 oral squamous cell carcinoma, 33 epithelial dysplasia, and 21 fibrous hyperplasia samples were immunohistochemically stained with anti-VDAC1 antibodies for semi-quantitative evaluation. The antibody detection was performed with 3,3′-diaminobenzidine (DAB). The clinicopathological information was examined for possible correlations with VDAC1. Results: VDAC1 expression was lower in oral squamous cell carcinoma 0.63 ± 0.40 and in oral epithelial dysplasia 0.61 ± 0.36 biopsies compared to fibrous hyperplasia biopsies 1.45 ± 0.28 (p < 0.01 for both; Kruskal–Wallis test). Conclusion: Oral squamous cell carcinoma and epithelial dysplasia tissues demonstrated decreased VDAC1 protein expression if compared to fibrous hyperplasia samples, but were not different from each other, suggesting that the involvement of VDAC1 in oral carcinogenesis is an early stage event, regulating cells to live or die.

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Pan-Cancer Analysis of Voltage-Dependent Anion Channel (VDAC1) as a Cancer Therapeutic Target or Diagnostic Biomarker

Cited by 9 publications

References 46 publications

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

VDAC1 selective molecules promote patients’-derived cancer organoids death through mitochondrial-dependent metabolic interference

Voltage-Dependent Anion Channel 1 Expression in Oral Malignant and Premalignant Lesions

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