{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:04:54Z","timestamp":1760234694919,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T00:00:00Z","timestamp":1623715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Fondazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG2018#22233"],"award-info":[{"award-number":["IG2018#22233"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003500","name":"Universit\u00e0 degli Studi di Padova","doi-asserted-by":"publisher","award":["SID19_01"],"award-info":[{"award-number":["SID19_01"]}],"id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["Ex60%"],"award-info":[{"award-number":["Ex60%"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009414","name":"Istituto Oncologico Veneto","doi-asserted-by":"publisher","award":["5X1000 Fund"],"award-info":[{"award-number":["5X1000 Fund"]}],"id":[{"id":"10.13039\/501100009414","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Numerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to metabolically adverse conditions, we executed quantitative phospho-proteomics in T-cell acute lymphoblastic leukemia (T-ALL) cells subjected to nutrient-depleted conditions (serum starvation). We found important modulations of peptides phosphorylated by critical signaling pathways including casein kinase, mammalian target of rapamycin, and 5\u2032AMP-activated kinase (AMPK). Surprisingly, in T-ALL cells, AMPK signaling was the most consistently downregulated pathway under serum-depleted conditions, and this coincided with increased GLI1 expression and sensitivity to iHHs, especially the GLI1\/2 inhibitor GANT-61. Increased sensitivity to GANT-61 was also found following genetic inactivation of the catalytic subunit of AMPK (AMPK\u03b11) or pharmacological inhibition of AMPK by Compound C. Additionally, patient-derived xenografts showing high GLI1 expression lacked activated AMPK, suggesting an important role for this signaling pathway in regulating GLI1 protein levels. Further, joint targeting of HH and AMPK signaling pathways in T-ALL cells by GANT-61 and Compound C significantly increased the therapeutic response. Our results suggest that metabolic adaptation that occurs under nutrient starvation in T-ALL cells increases responsiveness to HH pathway inhibitors through an AMPK-dependent mechanism and that joint therapeutic targeting of AMPK signaling and HH signaling could represent a valid therapeutic strategy in rapidly expanding tumors where nutrient availability becomes limiting.<\/jats:p>","DOI":"10.3390\/ijms22126384","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T11:00:33Z","timestamp":1623754833000},"page":"6384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5\u2032AMP-Activated Kinase Inactivation"],"prefix":"10.3390","volume":"22","author":[{"given":"Valeria","family":"Tosello","sequence":"first","affiliation":[{"name":"UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV\u2014IRCCS, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8693-4776","authenticated-orcid":false,"given":"Deborah","family":"Bongiovanni","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita\u2019 di Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludovica","family":"Di Martino","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita\u2019 di Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9223-117X","authenticated-orcid":false,"given":"Cinzia","family":"Franchin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"},{"name":"Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, 35129 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9996-2669","authenticated-orcid":false,"given":"Paola","family":"Zanovello","sequence":"additional","affiliation":[{"name":"UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV\u2014IRCCS, 35128 Padova, Italy"},{"name":"Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita\u2019 di Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4103-2733","authenticated-orcid":false,"given":"Giorgio","family":"Arrigoni","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"},{"name":"Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, 35129 Padova, Italy"},{"name":"CRIBI Biotechnology Center, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4241-563X","authenticated-orcid":false,"given":"Erich","family":"Piovan","sequence":"additional","affiliation":[{"name":"UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV\u2014IRCCS, 35128 Padova, Italy"},{"name":"Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita\u2019 di Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/nrc.2016.63","article-title":"The genetics and mechanisms of T cell acute lymphoblastic leukaemia","volume":"16","author":"Belver","year":"2016","journal-title":"Nat. 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