VDAC1 as a Player in Mitochondria-Mediated Apoptosis and Target for Modulating Apoptosis

Shoshan‐Barmatz, Varda; Krelin, Yakov; Chen, Quan

doi:10.2174/0929867324666170616105200

Cited by 52 publications

(51 citation statements)

References 95 publications

(183 reference statements)

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“…VDAC1, as mitochondrial gatekeeper, functions in energy production, Ca 2+ homeostasis, oxidative stress, and apoptosis and as a hub protein interacting with over 150 proteins, including anti‐apoptotic proteins (Shoshan‐Barmatz et al ., , ,b). Hence, targeting the interactions of VDAC1 with anti‐apoptotic proteins (Bcl‐2, Bcl‐xL) or proteins supporting the metabolic requirements of cancer cells (HK‐I, HK‐II) is a promising strategy for the development of anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

“…F); this precedes a decrease in cell viability (Machida et al ., ). Moreover, as the interaction of VDAC1 with HK mediates coupling between OXPHOS and glycolysis, enhanced cholesterol synthesis, decreased ROS production, and protection against apoptosis, disrupting this interaction should have multiple effects on cancer cells (Shoshan‐Barmatz et al ., , ,b). Accordingly, detachment of HK from VDAC1 represents a novel therapeutic strategy to impair cancer metabolism and augment apoptosis (Krasnov et al ., ; Shoshan‐Barmatz et al ., ).…”

Section: Discussionmentioning

confidence: 99%

“…It is now recognized that the OMM protein voltage‐dependent anion channel 1 (VDAC1) is a key player in mitochondria‐mediated apoptosis (Keinan et al ., ; Lemasters and Holmuhamedov, ; Shimizu et al ., ; Shoshan‐Barmatz et al ., , ). VDAC1 participates in the release of apoptotic proteins and regulates apoptosis through interactions with Bcl‐2 family proteins and hexokinase (HK) (Keinan et al ., ; Lemasters and Holmuhamedov, ; Shimizu et al ., ; Shoshan‐Barmatz et al ., , ). Indeed, accumulated findings indicate that both anti‐ and pro‐apoptotic proteins, including Bax, Bcl‐2, and Bcl‐xL, interact with VDAC1 to regulate mitochondria‐mediated apoptosis (Abu‐Hamad et al ., ; Arbel and Shoshan‐Barmatz, ; Arbel et al ., ; Malia and Wagner, ; Shi et al ., ; Shimizu et al ., , ; Shoshan‐Barmatz et al ., , ; Sugiyama et al ., ; Tajeddine et al ., ; Tsujimoto, ).…”

Section: Introductionmentioning

confidence: 99%

“…VDAC1 assumes a crucial position at the OMM, serving as the main interface between mitochondrial and cellular metabolisms, mediating the transport of anions, cations including Ca 2+ , ATP, and many metabolites between the mitochondria and the cytosol (Shoshan‐Barmatz et al ., ). Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to function as an anchoring site for a diverse set of cytosolic proteins, such as HK, tubulin, actin, and several dozen other proteins (Shoshan‐Barmatz et al ., ), that mediate metabolic and signaling cross talk between cytosol and mitochondria and regulate the integration of mitochondrial functions with other cellular activities (Shoshan‐Barmatz et al ., , ).…”

Section: Introductionmentioning

confidence: 99%

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Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy

et al. 2018

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Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites and serves as a key player in apoptosis. As such, VDAC1 is involved in two important hallmarks of cancer development, namely energy and metabolic reprograming and apoptotic cell death evasion. We previously developed cell‐penetrating VDAC1‐derived peptides that interact with hexokinase (HK), Bcl‐2, and Bcl‐xL to prevent the anti‐apoptotic activities of these proteins and induce cancer cell death, with a focus on leukemia and glioblastoma. In this study, we demonstrated the sensitivity of a panel of genetically characterized cancer cell lines, differing in origin and carried mutations, to VDAC1‐based peptide‐induced apoptosis. Noncancerous cell lines were less affected by the peptides. Furthermore, we constructed additional VDAC1‐based peptides with the aim of improving targeting, selectivity, and cellular stability, including R‐Tf‐D‐LP4, containing the transferrin receptor internalization sequence (Tf) that allows targeting of the peptide to cancer cells, known to overexpress the transferrin receptor. The mode of action of the VDAC1‐based peptides involves HK detachment, interfering with the action of anti‐apoptotic proteins, and thus activating multiple routes leading to an impairment of cell energy and metabolism homeostasis and the induction of apoptosis. Finally, in xenograft glioblastoma, lung, and breast cancer mouse models, R‐Tf‐D‐LP4 inhibited tumor growth while inducing massive cancer cell death, including of cancer stem cells. Thus, VDAC1‐based peptides offer an innovative new conceptual framework for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy

et al. 2018

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“…Apoptosis is involved many diseases, especially malignant tumors [30-32]. There are two major apoptotic pathways, namely, the extrinsic or death receptor pathway and intrinsic or mitochondrial pathways [33].…”

Section: Discussionmentioning

confidence: 99%

Chloroquine Enhances the Radiosensitivity of Bladder Cancer Cells by Inhibiting Autophagy and Activating Apoptosis

Wang

Tang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Chloroquine was formerly used as an anti-malarial agent drug but has now been proven to be useful for various diseases. This study aimed to investigate the radiosensitizing effect of chloroquine in bladder cancer, with an emphasis on autophagy inhibition and apoptosis induction. Methods: Bladder cancer cell lines were irradiated with or without chloroquine. Cell proliferation was determined by a Cell Counting Kit 8 assay. The radiosensitization effect of chloroquine was evaluated by clonogenic survival and progression of xenograft tumors. Cell apoptosis was detected by flow cytometry and western blot. Radiation-induced DNA double strand break was measured by the staining of γ-H2AX. In addition, autophagy was detected by western blot, immunofluorescence staining, and electron microscopy. Results: The treatment with chloroquine alone inhibited the proliferation of bladder cancer cells in a dose-dependent manner. Low cytotoxic concentrations of chloroquine enhanced the radiation sensitivity of bladder cancer cells with a sensitization enhancement ratio of 1.53 and 1.40. Chloroquine also obviously weakened the repair of radiation-induced DNA damage. A combination of radiation and chloroquine enhanced the apoptosis rate of EJ and T24 cells and down-regulated the expression of Bcl-2 while up-regulating the expression of caspase-3. Additionally, the relevant markers of autophagy were obviously increased in the combined group, meaning that chloroquine inhibited autophagy induced by irradiation. Furthermore, subcutaneous xenograft tumors displayed that the combination of radiation and chloroquine could impede tumorigenesis in vivo. Conclusion: In summary, these results provided support that by inhibiting autophagy and activating apoptosis, chloroquine might be a potentially promising radiosensitizer in the radiation therapy of bladder cancer.

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RETRACTED: Penfluridol triggers mitochondrial‐mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down‐regulating hexokinase‐2

Wang

Zhang

et al. 2020

The Anatomical Record

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Penfluridol, a commonly used antipsychotic agent in a clinical setting, exhibits potential anticancer properties against various human malignancies. Here, we investigated the effect of penfluridol on the biological behavior of colorectal cancer (CRC) cells. Cell viability and clonogenic potential were detected by the cell counting kit‐8 and colony formation assay. The cell apoptosis and cell cycle distribution were quantified through flow cytometry. Caspase‐3 activity, glucose consumption, lactate production, and intracellular ATP levels were evaluated using the corresponding commercial detection kits. The protein levels of related genes were detected through western blotting. Mitochondrial membrane potential was detected using JC‐1 staining. A CRC xenograft tumor model was used to validate the antitumor activity of penfluridol in vivo. Penfluridol reduced cell survival and promoted apoptotic cell death effectively through the mitochondria‐mediated intrinsic pathway in a dose‐dependent manner. Furthermore, the process of glycolysis in HCT‐116 and HT‐29 cells was inhibited upon penfluridol treatment, as evidenced by the decrease in glucose consumption, lactate production, and intracellular ATP levels. Further mechanistic studies revealed that penfluridol influenced cell apoptosis and glycolysis in CRC cells by downregulating hexokinase‐2 (HK‐2). The proapoptotic effect and glycolytic inhibition‐induced by penfluridol were effectively reversed by HK‐2 overexpression. Consistent with in vitro results, penfluridol could also suppress tumor growth and trigger apoptosis in vivo. Penfluridol triggers mitochondrial‐mediated apoptosis and induces glycolysis inhibition via modulating HK‐2 in CRC and provides a theoretical basis to support penfluridol as a repurposed drug for CRC patients.

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VDAC1 as a Player in Mitochondria-Mediated Apoptosis and Target for Modulating Apoptosis

Abstract: This review highlights the findings about VDAC1 oligomerization as a potential target for controlling apoptosis, specifically using drugs to induce apoptotic cell death in cancer and inhibit apoptosis in neurodegenerative diseases, as well as possible VDAC1-based therapeutic applications.

Cited by 52 publications

References 95 publications

Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy

Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy

Chloroquine Enhances the Radiosensitivity of Bladder Cancer Cells by Inhibiting Autophagy and Activating Apoptosis

RETRACTED: Penfluridol triggers mitochondrial‐mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down‐regulating hexokinase‐2

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