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Article

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

1
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
2
INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, 00078 Monte Porzio Catone (Rome), Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 5165; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145165
Received: 29 May 2020 / Revised: 18 July 2020 / Accepted: 20 July 2020 / Published: 21 July 2020
Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination. View Full-Text
Keywords: malignant pleural mesothelioma; CDK4/6 inhibition; Palbociclib; PI3K/mTOR inhibitors; metabolism malignant pleural mesothelioma; CDK4/6 inhibition; Palbociclib; PI3K/mTOR inhibitors; metabolism
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MDPI and ACS Style

Bonelli, M.; Terenziani, R.; Zoppi, S.; Fumarola, C.; La Monica, S.; Cretella, D.; Alfieri, R.; Cavazzoni, A.; Digiacomo, G.; Galetti, M.; Petronini, P.G. Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells. Int. J. Mol. Sci. 2020, 21, 5165. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145165

AMA Style

Bonelli M, Terenziani R, Zoppi S, Fumarola C, La Monica S, Cretella D, Alfieri R, Cavazzoni A, Digiacomo G, Galetti M, Petronini PG. Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells. International Journal of Molecular Sciences. 2020; 21(14):5165. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145165

Chicago/Turabian Style

Bonelli, Mara, Rita Terenziani, Silvia Zoppi, Claudia Fumarola, Silvia La Monica, Daniele Cretella, Roberta Alfieri, Andrea Cavazzoni, Graziana Digiacomo, Maricla Galetti, and Pier G. Petronini 2020. "Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells" International Journal of Molecular Sciences 21, no. 14: 5165. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145165

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