Journal Article

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

Papa, S, Palorini, R, Cirulli, C, Gaviraghi, M, Danna, L Sala, Signorile, A, De Rasmo, D, Chiaradonna, F, Alberghina, L

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/2327 / 631/67/395 / 631/80/642/333/1465 / 631/80/86 / Adaptations / Adenosine Triphosphate - biosynthesis / Animals / Antimitotic agents / Antineoplastic agents / Antitumor agents / Apoptosis / Apoptosis - drug effects / ATP / Cancer / Carcinogenesis / Cell Biology / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Respiration - drug effects / Cell Survival - drug effects / Cell Transformation, Neoplastic - drug effects / Colforsin - pharmacology / Cyclic adenylic acid / Cyclic AMP / Cyclic AMP - metabolism / Cyclic AMP-Dependent Protein Kinases - metabolism / Electron transport / Electron transport chain / Fibroblasts - cytology / Forskolin / Gene Expression Regulation, Neoplastic - drug effects / Genes, ras - genetics / Genetic engineering / Glucose / Glucose - pharmacology / Glycolysis / Health aspects / Human Genetics / Humans / Hypoxia / Internal Medicine / K-Ras protein / Medicine / Medicine & Public Health / Metastasis / Mice / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Morphology / NADH-ubiquinone oxidoreductase / Oncogenes / Oncology / original-article / Physiological aspects / Protein kinase A / Protein kinases / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal transduction / Signal Transduction - drug effects / Time Factors / Transformed cells