Aberrant activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway is one of the most frequent events in cancer, favoring metabolism reprogramming, sustained cell growth and multidrug and radiotherapy resistance. In this work we aimed to address the role of Akt1 in embryonal rhabdomyosarcoma (ERMS), the most frequent soft tissue sarcoma of the pediatric age arising from myogenic precursors. To do so, human embryonal RD cells were stably transfected with a myrystoilated Akt1 isoform (MyrAkt1), mimicking a constitutive activation of the PI3K/Akt signaling pathway. Indeed, MyrAkt1 clones showed enhanced Akt1 phosphorylation on S473 residue, followed by an increased phosphorylation of the canonical downstream GSK3β and p70/S6K proteins. The tumorigenic abilities of MyrAkt1 clones were augmented, as demonstrated by increased proliferation, migration and invasion capacity in vitro and in vivo, loss of myogenic potential and resistance to doxorubicin and ionizing radiation treatments through sustained activation of the DNA damage response pathway. Notably, we found that MyrAkt1 clones were characterized by a marked susceptibility to serum deprivation and metabolic agents, including inhibitors of glycolysis (2-deoxy-D-glucose), inhibitors of the mevalonate pathway (lovastatin) and inhibitors of the cystine uptake (erastin). Combined treatment using metabolic drugs together with doxorubicin or ionizing radiation exposure was able to sensitize MyrAkt1 clones to standard therapy. Overall, these data point out a role of Akt1 as master regulator of cellular metabolism in ERMS, whose overactivation could be exploited as a double-edged sword to target the Akt1-driven high metabolic demands. Future experiments will be focused on metabolic analysis to characterize the biochemical profile of MyrAkt1 clones.

Expression of a myrystoilated Akt1 isoform in rhabdomyosarcoma cells promotes chemo and radioresistance, but confers marked susceptibility to metabolic drug inhibitors

Silvia Codenotti;Samantha Contri;Daniela Zizioli;Eugenio Monti;Alessandro Fanzani.
2022

Abstract

Aberrant activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway is one of the most frequent events in cancer, favoring metabolism reprogramming, sustained cell growth and multidrug and radiotherapy resistance. In this work we aimed to address the role of Akt1 in embryonal rhabdomyosarcoma (ERMS), the most frequent soft tissue sarcoma of the pediatric age arising from myogenic precursors. To do so, human embryonal RD cells were stably transfected with a myrystoilated Akt1 isoform (MyrAkt1), mimicking a constitutive activation of the PI3K/Akt signaling pathway. Indeed, MyrAkt1 clones showed enhanced Akt1 phosphorylation on S473 residue, followed by an increased phosphorylation of the canonical downstream GSK3β and p70/S6K proteins. The tumorigenic abilities of MyrAkt1 clones were augmented, as demonstrated by increased proliferation, migration and invasion capacity in vitro and in vivo, loss of myogenic potential and resistance to doxorubicin and ionizing radiation treatments through sustained activation of the DNA damage response pathway. Notably, we found that MyrAkt1 clones were characterized by a marked susceptibility to serum deprivation and metabolic agents, including inhibitors of glycolysis (2-deoxy-D-glucose), inhibitors of the mevalonate pathway (lovastatin) and inhibitors of the cystine uptake (erastin). Combined treatment using metabolic drugs together with doxorubicin or ionizing radiation exposure was able to sensitize MyrAkt1 clones to standard therapy. Overall, these data point out a role of Akt1 as master regulator of cellular metabolism in ERMS, whose overactivation could be exploited as a double-edged sword to target the Akt1-driven high metabolic demands. Future experiments will be focused on metabolic analysis to characterize the biochemical profile of MyrAkt1 clones.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/557858
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