title: Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis.
abstract: 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.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO Center for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|Luxembourg Centre for Systems Biomedicine, Esch-sur-Alzette, Luxembourg.
authors.forename: Roberta
authors.initials: R
authors.lastname: Palorini
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO Center for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Votta
authors.affiliation: Department of Informatics Systems and Communication, University of Milano-Bicocca, Milan, Italy.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pirola
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Humberto
authors.initials: H
authors.lastname: De Vitto
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate-Cefalù, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: De Palma
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate-Cefalù, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Vasso
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricciardiello
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Pietro Paolo
authors.initials: PP
authors.lastname: Lombardi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cirulli
authors.affiliation: Department of Informatics Systems and Communication, University of Milano-Bicocca, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rizzi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicotra
authors.affiliation: Luxembourg Centre for Systems Biomedicine, Esch-sur-Alzette, Luxembourg.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate-Cefalù, Italy.|Department of Biomedical Sciences for Health, University of Milan, Segrate, Milan, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gelfi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO Center for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Lilia
authors.initials: L
authors.lastname: Alberghina
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO Center for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Chiaradonna
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D000242:Cyclic AMP / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D013217:Starvation; D059467:Transcriptome
chemical_list: D005973:Glutamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose