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2. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation

Author

Cecconi, Francesco, Cianfanelli, Valentina, Fuoco, Claudia, Lorente Pérez, María Del Mar, Salazar Roa, María, Quondamatteo, Fabio, Gherardini, Pier Federico, De Zio, Daniela, Nazio, Francesca, Antonioli, Manuela, D’Orazio, Melania, Skobo, Tatjana, Bordi, Matteo, Rohde, Mikkel, Dalla Valle, Luisa, Helmer-Citterich, Manuela, Gretzmeier, Christine, Dengjel, Joern, Fimia, Gian Maria, Piacentini, Mauro, Di Bartolomeo, Sabrina, Velasco Díez, Guillermo, Cecconi, Francesco, Cianfanelli, Valentina, Fuoco, Claudia, Lorente Pérez, María Del Mar, Salazar Roa, María, Quondamatteo, Fabio, Gherardini, Pier Federico, De Zio, Daniela, Nazio, Francesca, Antonioli, Manuela, D’Orazio, Melania, Skobo, Tatjana, Bordi, Matteo, Rohde, Mikkel, Dalla Valle, Luisa, Helmer-Citterich, Manuela, Gretzmeier, Christine, Dengjel, Joern, Fimia, Gian Maria, Piacentini, Mauro, Di Bartolomeo, Sabrina, and Velasco Díez, Guillermo

Abstract

Acknowledgements We wish to thank M. Canney, V. Unterkircher, R. Laricchia and M. Salomé for excellent technical assistance, and M. Acuña Villa and M. W. Bennett for editorial and secretarial work. We also thank S. Campello for critical reading of the manuscript. We are indebted to R. Sears (Portland, Oregon, USA), A. C. Gingras (Toronto, Canada) and A. Teleman and K. Dimitriadis (Heidelberg, Germany) for providing us with V5–Flag–c-Myc and Flag–PR65A constructs and Tsc2 MEFs, respectively, and to S. Cannata (Rome) for his advice on histopathology. This work was supported by grants from KBVU (R72-A4408), Lundbeck Foundation (R167-2013-16100), Novo Nordisk Foundation (7559), The Bjarne Saxhof Foundation, AIRC (IG2010 and IG2012 to both F.C. and M.P.), and in part from FISM (2009), the Telethon Foundation (GGP10225), the Italian Ministry of University and Research (PRIN 2009 and FIRB Accordi di Programma 2011) and the Italian Ministry of Health (RF 2009). V.C. is supported by the Lundbeck Foundation (R165-2013-15982). Also, we are grateful to the Spanish Ministry of Economy and Competitiveness (MINECO) (PS09/01401; PI12/02248, FR2009-0052 and IT2009-0053) and to Fundación Mutua Madrileña (AP101042012) for funding the laboratory of G.V., Inhibition of a main regulator of cell metabolism, the protein kinase mTOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these two mTOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA1, a member of the autophagy signalling network and a downstream target of mTOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene., Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, TRUE, pub

Published
2024
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3. AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.

Author

Di Leo L, Pagliuca C, Kishk A, Rizza S, Tsiavou C, Pecorari C, Dahl C, Pacheco MP, Tholstrup R, Brewer JR, Berico P, Hernando E, Cecconi F, Ballotti R, Bertolotto C, Filomeni G, Gjerstorff MF, Sauter T, Lovat P, Guldberg P, and De Zio D

Subjects
Humans, Cell Line, Tumor, Animals, Mice, Focal Adhesion Kinase 1 metabolism, Focal Adhesion Kinase 1 antagonists & inhibitors, Xenograft Model Antitumor Assays, Mitogen-Activated Protein Kinases metabolism, Gene Expression Regulation, Neoplastic drug effects, Female, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics
Abstract

Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1 expression exhibit intrinsic resistance to MAPKi therapy but higher sensitivity to FAK1 inhibition. Finally, we show that the rapid development of resistance in initially MAPKi-sensitive melanomas can be attributed to preexisting subclones characterized by low AMBRA1 expression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi) effectively prevents the development of resistance in these tumors. In summary, our findings underscore the value of AMBRA1 expression for predicting melanoma response to MAPKi and supporting the therapeutic efficacy of FAKi to overcome MAPKi-induced resistance., Competing Interests: Competing interests statement:P.L. is Chief Scientific Officer for AMLo Biosciences Ltd.

Published
2024
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