Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation

Huang, Huiya; Shah, Kalpit; Bradbury, Neil A.; Li, C; White, Carl

doi:10.1038/cddis.2014.419

Cited by 125 publications

(117 citation statements)

References 55 publications

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“…Finally, in contrast to our findings and those of others (26,62), recent reports indicated that anti-apoptotic Bcl-XL and Mcl-1 are both able to enhance VDAC1-mediated Ca 2ϩ transfer into the mitochondria under some conditions (51,63). Indeed, their overexpression enhanced while their deficiency suppressed mitochondrial Ca 2ϩ uptake (51,63).…”

Section: Discussioncontrasting

confidence: 56%

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The BH4 Domain of Anti-apoptotic Bcl-XL, but Not That of the Related Bcl-2, Limits the Voltage-dependent Anion Channel 1 (VDAC1)-mediated Transfer of Pro-apoptotic Ca2+ Signals to Mitochondria

Monaco

Decrock

Arbel

et al. 2015

Journal of Biological Chemistry

111

101

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Background: VDAC1 mediates the transfer of pro-apoptotic Ca 2ϩ signals into mitochondria. Results: The BH4 domain of Bcl-XL, but not that of Bcl-2, targets VDAC1 and suppresses its pro-apoptotic Ca 2ϩ -flux properties. N-terminal VDAC1 peptide alleviates this effect of BH4-Bcl-XL. Conclusion: Bcl-XL via its BH4 domain inhibits VDAC1 activity. Significance: Bcl-2 and Bcl-XL differ in their BH4 domain biology by regulating ER and mitochondrial Ca 2ϩ -transport systems, respectively.

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Section: Discussioncontrasting

confidence: 56%

“…Indeed, their overexpression enhanced while their deficiency suppressed mitochondrial Ca 2ϩ uptake (51,63). These effects were not observed in VDAC1-deficient cells and were counteracted by N-terminal VDAC1-derived peptides (51,63).…”

Section: Discussionmentioning

confidence: 81%

The BH4 Domain of Anti-apoptotic Bcl-XL, but Not That of the Related Bcl-2, Limits the Voltage-dependent Anion Channel 1 (VDAC1)-mediated Transfer of Pro-apoptotic Ca2+ Signals to Mitochondria

Monaco

Decrock

Arbel

et al. 2015

Journal of Biological Chemistry

111

101

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“…VDAC1 and VDAC2 are the main isoforms in most mammalian cells, including cancer cells in which they account for up to 90% of the total. The least abundant isoform, VDAC3, comprising the remaining 10% (De Pinto et al, 2010; Huang, Shah, Bradbury, Li, & White, 2014; Maldonado et al, 2013) is abundant only in testis (Sampson et al, 2001; Sampson, Lovell, & Craigen, 1997). …”

Section: Vdac Channels and Mitochondrial Metabolismmentioning

confidence: 99%

VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation

Fang

Maldonado

2018

Advances in Cancer Research

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Cancer metabolism is emerging as a chemotherapeutic target. Enhanced glycolysis and suppression of mitochondrial metabolism characterize the Warburg phenotype in cancer cells. The flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol occur through voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane. Catabolism of respiratory substrates in the Krebs cycle generates NADH and FADH2 that enter the electron transport chain (ETC) to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The ETC is also the major cellular source of mitochondrial reactive oxygen species (ROS). αβ-Tubulin heterodimers decrease VDAC conductance in lipid bilayers. High constitutive levels of cytosolic free tubulin in intact cancer cells close VDAC decreasing mitochondrial ΔΨ and mitochondrial metabolism. The VDAC–tubulin interaction regulates VDAC opening and globally controls mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a VDAC-binding molecule lethal to some cancer cell types, and erastin-like compounds identified in a high-throughput screening antagonize the inhibitory effect of tubulin on VDAC. Reversal of tubulin inhibition of VDAC increases VDAC conductance and the flux of metabolites into and out of mitochondria. VDAC opening promotes a higher mitochondrial ΔΨ and a global increase in mitochondrial metabolism leading to high cytosolic ATP/ADP ratios that inhibit glycolysis. VDAC opening also increases ROS production causing oxidative stress that, in turn, leads to mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of the VDAC–tubulin interaction promotes cell death by a “double-hit model” characterized by reversion of the proproliferative Warburg phenotype (anti-Warburg) and promotion of oxidative stress.

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“…In NSCLC, Bcl-2, Bcl-xl and Mcl-1 are often found to be upregulated, which is associated with chemotherapy resistance and metastasis of cancers [11, 12]. These findings indicate that suppression of the anti-apoptotic Bcl-2 proteins may be a promising strategy for cancer therapy and potentially overcome the resistance to conventional chemotherapy.…”

Section: Introductionmentioning

confidence: 97%

Degradation of Mcl-1 through GSK-3β Activation Regulates Apoptosis Induced by Bufalin in Non-Small Cell Lung Cancer H1975 Cells

Kang

Zhang

Qing-qin

et al. 2017

Cell Physiol Biochem

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Background/Aims: Mcl-1, an anti-apoptotic Bcl-2 family member, is often overexpressed in non-small cell lung cancer (NSCLC). Bufalin has been reported to induce apoptosis in various tumor cells. However, there is no report showing that bufalin could downregulate Mcl-1 expression in NSCLC. Methods: Cell proliferation was analyzed by cell counting kit-8 (CCK-8) assay in H1975 cells. Cell apoptosis was detected by flow cytometry. Mcl-1 mRNA was detected by RT-PCR. The expression of apoptosis-associated proteins in H1975 cells was detected by western blotting. The levels of Mcl-1 ubiquitination and NOXA were analyzed by Immunoprecipitation assay. Results: Cell growth was inhibited by bufalin in a time and dose-dependent manner. Bufalin induced apoptosis in NSCLC cells by activating caspase cascades and downregulating Mcl-1 expression. However, overexpression of Mcl-1 diminished bufalin-induced apoptosis. Furthermore, bufalin did not reduce Mcl-1 mRNA expression in H1975 cells, but strongly promoted Mcl-1 protein degradation. Proteasome inhibitor MG132 markedly prevented the degradation of Mcl-1 and blocked bufalin-induced Mcl-1 reduction. Bufalin did not significantly affect NOXA protein levels, but downregulated the expression of p-GSK-3β. GSK-3 inhibitor and GSK-3β siRNA resulted in increased levels of Mcl-1 and reversed the bufalin-induced Mcl-1 degradation. Conclusion: Bufalin induced cell apoptosis in H1975 cells may be through downregulation of Mcl-1. Proteasomal degradation of Mcl-1 via GSK-3β activation was involved in bufalin-induced apoptosis.

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Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation

Cited by 125 publications

References 55 publications

The BH4 Domain of Anti-apoptotic Bcl-XL, but Not That of the Related Bcl-2, Limits the Voltage-dependent Anion Channel 1 (VDAC1)-mediated Transfer of Pro-apoptotic Ca2+ Signals to Mitochondria

The BH4 Domain of Anti-apoptotic Bcl-XL, but Not That of the Related Bcl-2, Limits the Voltage-dependent Anion Channel 1 (VDAC1)-mediated Transfer of Pro-apoptotic Ca2+ Signals to Mitochondria

VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation

Degradation of Mcl-1 through GSK-3β Activation Regulates Apoptosis Induced by Bufalin in Non-Small Cell Lung Cancer H1975 Cells

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