Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis

Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acqu...

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Published in:	PLoS genetics Vol. 12; no. 3; p. e1005931
Main Authors:	Palorini, Roberta, Votta, Giuseppina, Pirola, Yuri, De Vitto, Humberto, De Palma, Sara, Airoldi, Cristina, Vasso, Michele, Ricciardiello, Francesca, Lombardi, Pietro Paolo, Cirulli, Claudia, Rizzi, Raffaella, Nicotra, Francesco, Hiller, Karsten, Gelfi, Cecilia, Alberghina, Lilia, Chiaradonna, Ferdinando
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 15-03-2016 Public Library of Science (PLoS)
Subjects:	Animals Anoikis - genetics Apoptosis Autophagy Autophagy - genetics Biology and Life Sciences Cancer Cancer cells Cancer therapies Cell adhesion & migration Cell growth Cell Line, Tumor Cell Survival - genetics Cyclic AMP - genetics Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - biosynthesis Cyclic AMP-Dependent Protein Kinases - genetics Datasets Endoplasmic reticulum Endoplasmic Reticulum Stress Gene expression Genetic aspects Glucose - deficiency Glucose - metabolism Glutamine - metabolism Glycolysis Grants Growth Health aspects Humans Kinases Mass spectrometry Medicine and Health Sciences Metabolism Metabolites Mice Neoplasms - genetics Neoplasms - metabolism Physical Sciences Properties Protein kinases Proteins Scientific imaging Starvation Transcriptome
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Summary:	Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: RP GV FC CA CG. Performed the experiments: RP GV YP HDV SDP CA MV FR PPL CC. Analyzed the data: RP GV YP HDV SDP CA MV FR CC RR CG KH FC. Contributed reagents/materials/analysis tools: YP RR FN KH CG LA FC. Wrote the paper: RP GV YP HDV KH FC. Conceived and supervised the project: FC. Wrote the draft: FC. The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1005931