Mitochondrial proteins (e.g. VDAC, Bcl-2, HK, ANT2...) as major control points in oncology

Editors

Catherine Brenner

METSY CNRS UMR 9018 - Gustave Roussy - Univerisity of Paris-Saclay

Impact

Review

07 March 2013

Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology

Gopinath Sutendra

and

Evangelos D. Michelakis

38,812 views

226 citations

Reactive oxygen species occlusion and degradation in mitochondria can prevent cell damage. A schematic presentation summarizing current knowledge and proposed control mechanisms for ROS production, neutralization, and cellular effects (see VDAC1 Function in ROS Release, ROS-mediated Apoptosis and Interaction with NO). Free radicals generated by the electron transport chain are generally regarded as toxic metabolites and, as such, are degraded by specialized enzymes, namely catalases, peroxidases, superoxide dismutases, and glutathione peroxidase. Mitochondrial ROS cross the OMM via VDAC. The ROS that escapes catalytic removal can cause oxidative damage () to mitochondria, and when released from the mitochondria, can damage cellular proteins, lipids, and DNA. In addition, ROS can induce apoptosis. ROS is proposed to induce Cyto c release by oxidizing the mitochondria-specific phospholipid, cardiolipin (CL). ROS-oxidized CL has a markedly lower affinity for Cyto c, thus rendering Cyto c free in the inter-membrane space. ROS can also induce VDAC oligomerization to yield a mega-channel mediating Cyto c release. VDAC inhibitors (e.g., RuR, AzRu, DIDS) and hexokinase (HK) can prevent ROS release to the cytosol. CuZnSOD, cytosolic (copper–zinc-containing) superoxide dismutases; MnSOD, mitochondrial (manganese-containing) superoxide dismutases; GPx, glutathione peroxidase.

Review

29 November 2012

VDAC1: from structure to cancer therapy

Varda Shoshan-Barmatz

and

Dario Mizrachi

24,624 views

170 citations

Review

08 March 2013

Mitochondrial permeability transition pore as a selective target for anti-cancer therapy

Dong H. Suh

, 3 more and

Yong S. Song

10,707 views

68 citations

Molecular mechanisms elicited by the recently synthesized gold-compound AUL12 to specifically induce cell death of tumor cells. AUL12 inhibits the complex I of the mitochondrial respiratory chain thus eliciting an increase in ROS levels. The ROS surge reactivates the oncogenically inhibited GSK-3; mitochondrial GSK-3 phosphorylates CyP-D, unlocking the PTP blocked by oncogene signaling; cytosolic GSK-3 binds to and phosphorylates Bax, leading to its mitochondrial translocation. Mitochondrial Bax prompts mitochondrial permeabilization at least partially by inducing the PTP.

Mini Review

05 February 2013

GSK-3 and mitochondria in cancer cells

Federica Chiara

and

Andrea Rasola

11,759 views

59 citations

Proposed mechanisms of inhibitory effects of PP on the proliferation of myeloma/erythroleukemia cells. IL-6 binds to its transmembrane receptor (IL-6R) and activates JAK2, which phosphorylates STAT3. Tyr705-phosphorylated STAT3 (P-STAT3) translocates to the nucleus and activates transcription of Bcl-XL, Bcl-2, and cyclin D1, thereby inhibiting apoptosis and inducing cell cycle progression of myeloma/erythroleukemia cells. PP inhibits mitochondrial electron-transport chain complex I and activates AMPK to inhibit STAT3-Tyr705 phosphorylation (Harada et al., 2012).

Mini Review

02 October 2012

Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration

Isao Ishii

, 1 more and

Tadashi Kasahara

11,454 views

53 citations

Scheme of PI3K/Akt/mTOR-imposed antiapoptotic signaling at the mitochondria. See text for details.

Review

08 October 2012

Shifting the balance of mitochondrial apoptosis: therapeutic perspectives

Simone Fulda

5,566 views

22 citations

Review

02 January 2013

Crosstalk between Bcl-2 family and Ras family small GTPases: potential cell fate regulation?

Jia Kang

and

Shazib Pervaiz

4,565 views

23 citations

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