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Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration

Oncogene volume 32, pages 352–362 (2013)Cite this article

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Abstract

The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that K-ras transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of PKA activity, achieved by forskolin treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the PKA activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs.

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Acknowledgements

This work has been supported by a grant to LA from MIUR (FIRB-ITALBIONET), grants to FC from the Italian Government (FAR) and MIUR (Prin 2008), grant to DDR and CC from MIUR (Progetto FIRB futuro in ricerca, 2008), grants to SP from MIUR (Progetto FIRB Rete Nazionale per lo Studio della Proteomica Umana-Italian Human ProteomeNet, 2009) and Progetto Strategico Ric.002, Cip PS 101, POR 2000/06.

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  1. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy

    R Palorini, M Gaviraghi, L Sala Danna, C Cirulli, F Chiaradonna & L Alberghina

  2. Department of Medical Biochemistry, Biology and Physics (DIBIFIM), University of Bari, Bari, Italy

    D De Rasmo, A Signorile & S Papa

  3. Institute of Biomembranes and Bioenergetics (IBBE), Consiglio Nazionale delle Ricerche, Bari, Italy

    D De Rasmo & S Papa

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  1. R Palorini
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Palorini, R., De Rasmo, D., Gaviraghi, M. et al. Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration. Oncogene 32, 352–362 (2013). https://doi.org/10.1038/onc.2012.50

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