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Vatrinet 2015 Abstract MiP2015

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Targeting complex I as an anticancer strategy.


Vatrinet R, Kurelac I, Iommarini L, Amato L, De Luise M, Leone G, Vidali S, Kofler B, Gasparre G, Porcelli AM (2015)

Event: MiP2015

Tumor cells exhibit profound bioenergetic changes with respect to the original non-transformed cell types [1]. One of the main driving mechanisms leading to such a metabolic alteration is triggered by hypoxia. Hypoxia is experienced by cancer cells during tumor progression and leads to a significant enhancement of glycolysis in order to sustain tumor growth and survival [2].

Notwithstanding low oxygen conditions, cancer cells harboring mitochondrial respiratory complex I (CI) disruptive mutations displayed a chronic destabilization (pseudonormoxia) of hypoxia inducible factor 1α (HIF1α), the main factor driving the hypoxic response. Such genetic lesions are associated with a significant reduction of the tumorigenic potential in vivo, suggesting an inability to adapt to environmental changes [3]. Therefore, dissecting the mechanisms by which complex I severe impairment causes HIF1α destabilization will help identifying new targets for potential anticancer strategies.

Using the zinc finger nucleases technology, we have generated NDUFS3-deficient cancer cells which display a marked CI deficiency. Engineered CI-defective cancer cells show a lack of HIF1α stabilization in hypoxic condition together with a significant reduction of the expression of HIF1α -responsive genes involved in the glycolytic machinery and tumor vascularization. These changes are associated with imbalanced Krebs’ cycle metabolites and, in particular, with an accumulation of α-ketoglutarate, known to foster the activity of the prolyl hydroxylases (PHDs) leading to HIF1α proteasomal degradation. Moreover, CI-defective cancer cells show a significant reduction of the tumorigenic potential in vitro and in vivo.

Hence, targeting the mitochondrial respiratory CI confers antitumorigenic properties by preventing the stabilization of HIF1α, thus hindering cancer cells adaptation to hypoxia. Further analyses will help confirm the pivotal role of PHDs in our current model.

O2k-Network Lab: AT Salzburg Sperl W

Labels: MiParea: nDNA;cell genetics, Genetic knockout;overexpression, mt-Medicine  Pathology: Cancer  Stress:Oxidative stress;RONS  Organism: Human 

Enzyme: Complex I 

Event: A2, Oral  MiP2015 


1-FABIT, Dept Farmacia Biotecnologie, Univ Bologna; 2-DIMEC, UO Genetica Medica, Pol Univ S Orsola-Malpighi; 3-SALK, Bologna, Italia. -

References and acknowledgements

  1. Hanhan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646-74.
  2. Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. BBRC 16:459-65.
  3. Calabrese C, Iommarini L, Kurelac I, Calvaruso MA, Capristo M, Lollini PL, Nanni P, Bergamini C, Nicoletti G, Giovanni CD, Ghelli A, Giorgio V, Caratozzolo MF, Marzano F, Manzari C, Betts CM, Carelli V, Ceccarelli C, Attimonelli M, Romeo G, Fato R, Rugolo M, Tullo A, Gasparre G, Porcelli AM (2013) Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells. Cancer Metab 1:11

This work is funded by the Italian Association for Cancer Research (AIRC) IG-14242 and by the EU FP7 Marie Curie project MEET 317433.