{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T23:20:41Z","timestamp":1777418441756,"version":"3.51.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"5-6","license":[{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Hungarian National Government and University of Pecs","award":["TUDFO\/51757-1\/2019-ITM"],"award-info":[{"award-number":["TUDFO\/51757-1\/2019-ITM"]}]},{"name":"Hungarian National Government","award":["EFOP-3.6.1-16-2016-00004"],"award-info":[{"award-number":["EFOP-3.6.1-16-2016-00004"]}]},{"name":"Hungarian National Government","award":["GINOP 2.3.2-15-2016-00022"],"award-info":[{"award-number":["GINOP 2.3.2-15-2016-00022"]}]},{"name":"University of Pecs","award":["Szentagothai Research Centre 2020"],"award-info":[{"award-number":["Szentagothai Research Centre 2020"]}]},{"DOI":"10.13039\/501100009594","name":"University of P\u00e9cs","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009594","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Apoptosis"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tuberous sclerosis, angiomyolipoma and lymphangioleiomyomatosis are a group of diseases characterized by mutation in tuberous sclerosis genes (TSC 1-2). TSC mutation leads to continuous activation of the mTOR pathway that requires adaptation to increased ATP requirement. With limited treatment options, there is an increasing demand to identify novel therapeutic targets and to understand the correlations between mTOR pathway activation and the lack of cell death in the presence of TSC mutation. In the current study, we demonstrate deregulation of p53 controlled and mitochondria associated cell death processes. The study also reveals that treatment of TSC mutant cells with the drug candidate Proxison combined with reduced concentration of rapamycin can increase production of reactive oxygen species (ROS), can modify miRNA expression pattern associated with p53 regulation and can reduce cell viability.<\/jats:p>","DOI":"10.1007\/s10495-021-01670-4","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T05:43:43Z","timestamp":1618551823000},"page":"253-260","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited"],"prefix":"10.1007","volume":"26","author":[{"given":"ElHusseiny M. M.","family":"Abdelwahab","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Bovari-Biri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabor","family":"Smuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janos","family":"Fillinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald","family":"McPhail","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera P.","family":"Krymskaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0278-5556","authenticated-orcid":false,"given":"Judit E.","family":"Pongracz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"1670_CR1","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.3390\/ijms17122068","volume":"17","author":"A Ranjan","year":"2016","unstructured":"Ranjan A, Iwakuma T (2016) Non-canonical cell death induced by p53. Int J Mol Sci 17:2068","journal-title":"Int J Mol Sci"},{"key":"1670_CR2","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/biom8020014","volume":"8","author":"M Mrakovcic","year":"2018","unstructured":"Mrakovcic M, Fr\u00f6hlich LF (2018) P53-mediated molecular control of autophagy in tumor cells. Biomolecules 8:14","journal-title":"Biomolecules"},{"key":"1670_CR3","doi-asserted-by":"publisher","first-page":"3093","DOI":"10.1038\/s41388-018-0625-1","volume":"38","author":"EMM Abdelwahab","year":"2019","unstructured":"Abdelwahab EMM, Pal S, Kvell K et al (2019) Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target. Oncogene 38:3093\u20133101. https:\/\/doi.org\/10.1038\/s41388-018-0625-1","journal-title":"Oncogene"},{"key":"1670_CR4","doi-asserted-by":"publisher","DOI":"10.1002\/mc.20628","author":"X-G Chen","year":"2010","unstructured":"Chen X-G, Liu F, Song X-F et al (2010) Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways. Mol Carcinog. https:\/\/doi.org\/10.1002\/mc.20628","journal-title":"Mol Carcinog"},{"key":"1670_CR5","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/J.CELL.2017.02.004","volume":"168","author":"RA Saxton","year":"2017","unstructured":"Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960\u2013976. https:\/\/doi.org\/10.1016\/J.CELL.2017.02.004","journal-title":"Cell"},{"key":"1670_CR6","doi-asserted-by":"publisher","first-page":"20","DOI":"10.4161\/cc.22912","volume":"12","author":"P Hasty","year":"2013","unstructured":"Hasty P, Sharp ZD, Curiel TJ, Campisi J (2013) mTORC1 and p53: clash of the gods? Cell Cycle 12:20\u201325","journal-title":"Cell Cycle"},{"key":"1670_CR7","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1146\/annurev-med-050715-104245","volume":"68","author":"VP Krymskaya","year":"2017","unstructured":"Krymskaya VP, McCormack FX (2017) Lymphangioleiomyomatosis: a monogenic model of malignancy. Annu Rev Med 68:69\u201383. https:\/\/doi.org\/10.1146\/annurev-med-050715-104245","journal-title":"Annu Rev Med"},{"key":"1670_CR8","doi-asserted-by":"publisher","first-page":"755","DOI":"10.3390\/ijms20030755","volume":"20","author":"T Tian","year":"2019","unstructured":"Tian T, Li X, Zhang J (2019) mTOR signaling in cancer and mtor inhibitors in solid tumor targeting therapy. Int J Mol Sci 20:755","journal-title":"Int J Mol Sci"},{"key":"1670_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-018-0775-9","volume":"13","author":"Y Zhan","year":"2018","unstructured":"Zhan Y, Shen L, Xu W et al (2018) Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study. Orphanet J Rare Dis 13:1\u20138. https:\/\/doi.org\/10.1186\/s13023-018-0775-9","journal-title":"Orphanet J Rare Dis"},{"key":"1670_CR10","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1016\/j.healun.2007.09.013","volume":"26","author":"JR Maurer","year":"2007","unstructured":"Maurer JR, Ryu J, Beck G et al (2007) Lung transplantation in the management of patients with lymphangioleiomyomatosis: baseline data from the NHLBI LAM registry. J Hear Lung Transplant 26:1293\u20131299. https:\/\/doi.org\/10.1016\/j.healun.2007.09.013","journal-title":"J Hear Lung Transplant"},{"key":"1670_CR11","doi-asserted-by":"publisher","first-page":"30958","DOI":"10.1074\/jbc.M202678200","volume":"277","author":"EA Goncharova","year":"2002","unstructured":"Goncharova EA, Goncharov DA, Eszterhas A et al (2002) Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 277:30958\u201330967. https:\/\/doi.org\/10.1074\/jbc.M202678200","journal-title":"J Biol Chem"},{"key":"1670_CR12","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1016\/j.ajpath.2016.03.009","volume":"186","author":"M Yue","year":"2016","unstructured":"Yue M, Pacheco G, Cheng T et al (2016) Evidence supporting a lymphatic endothelium origin for angiomyolipoma, a TSC2\u2212 tumor related to lymphangioleiomyomatosis. Am J Pathol 186:1825\u20131836. https:\/\/doi.org\/10.1016\/j.ajpath.2016.03.009","journal-title":"Am J Pathol"},{"key":"1670_CR13","doi-asserted-by":"publisher","DOI":"10.1177\/1947601912445376","author":"SL Habib","year":"2011","unstructured":"Habib SL, Yadav A, Mahimainathan L, Valente AJ (2011) Regulation of PI 3-K, PTEN, p53, and mTOR in malignant and benign tumors deficient in tuberin. Genes Cancer. https:\/\/doi.org\/10.1177\/1947601912445376","journal-title":"Genes Cancer"},{"key":"1670_CR14","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx345","author":"LC Armstrong","year":"2017","unstructured":"Armstrong LC, Westlake G, Snow JP et al (2017) Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming. Hum Mol Genet. https:\/\/doi.org\/10.1093\/hmg\/ddx345","journal-title":"Hum Mol Genet"},{"key":"1670_CR15","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.molmed.2010.09.002","volume":"16","author":"C Dai","year":"2010","unstructured":"Dai C, Gu W (2010) P53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med 16:528\u2013536","journal-title":"Trends Mol Med"},{"key":"1670_CR16","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1186\/gb-2008-9-s1-s4","volume":"9","author":"S Mostafavi","year":"2008","unstructured":"Mostafavi S, Ray D, Warde-Farley D et al (2008) GeneMANIA: a real-time multiple association network integration algorithm for predicting gene function. Genome Biol 9:S4. https:\/\/doi.org\/10.1186\/gb-2008-9-s1-s4","journal-title":"Genome Biol"},{"key":"1670_CR17","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1146\/annurev-genet-102108-134850","volume":"43","author":"C Wang","year":"2009","unstructured":"Wang C, Youle RJ (2009) The role of mitochondria. Annu Rev Genet 43:95\u2013118. https:\/\/doi.org\/10.1146\/annurev-genet-102108-134850","journal-title":"Annu Rev Genet"},{"key":"1670_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep16422","volume":"5","author":"J Li","year":"2015","unstructured":"Li J, Aung LHH, Long B et al (2015) MiR-23a binds to p53 and enhances its association with miR-128 promoter. Sci Rep 5:1\u201313. https:\/\/doi.org\/10.1038\/srep16422","journal-title":"Sci Rep"},{"key":"1670_CR19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.bbamcr.2008.05.013","volume":"1793","author":"C Merkwirth","year":"2009","unstructured":"Merkwirth C, Langer T (2009) Prohibitin function within mitochondria: Essential roles for cell proliferation and cristae morphogenesis. Biochim Biophys Acta 1793:27\u201332","journal-title":"Biochim Biophys Acta"},{"key":"1670_CR20","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1152\/physrev.00026.2013","volume":"94","author":"DB Zorov","year":"2014","unstructured":"Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94:909\u2013950","journal-title":"Physiol Rev"},{"key":"1670_CR21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050683","author":"P Lopert","year":"2012","unstructured":"Lopert P, Day BJ, Patel M (2012) Thioredoxin reductase deficiency potentiates oxidative stress, mitochondrial dysfunction and cell death in dopaminergic cells. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0050683","journal-title":"PLoS ONE"},{"key":"1670_CR22","doi-asserted-by":"publisher","first-page":"11857","DOI":"10.1038\/s41598-017-12072-5","volume":"7","author":"NJ Drummond","year":"2017","unstructured":"Drummond NJ, Davies NO, Lovett JE et al (2017) A synthetic cell permeable antioxidant protects neurons against acute oxidative stress. Sci Rep 7:11857. https:\/\/doi.org\/10.1038\/s41598-017-12072-5","journal-title":"Sci Rep"},{"key":"1670_CR23","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1007\/s00726-010-0514-6","volume":"41","author":"G Berge","year":"2011","unstructured":"Berge G, Costea DE, Berg M et al (2011) Coexpression and nuclear colocalization of metastasis-promoting protein S100A4 and p53 without mutual regulation in colorectal carcinoma. Amino Acids 41:875\u2013884. https:\/\/doi.org\/10.1007\/s00726-010-0514-6","journal-title":"Amino Acids"},{"key":"1670_CR24","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1242\/jcs.051011","volume":"122","author":"M Laplante","year":"2009","unstructured":"Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589\u20133594. https:\/\/doi.org\/10.1242\/jcs.051011","journal-title":"J Cell Sci"},{"key":"1670_CR25","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1158\/0008-5472.CAN-18-0717","volume":"79","author":"BL Allen-Petersen","year":"2019","unstructured":"Allen-Petersen BL, Risom T, Feng Z et al (2019) Activation of PP2A and inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma. Cancer Res 79:209\u2013219. https:\/\/doi.org\/10.1158\/0008-5472.CAN-18-0717","journal-title":"Cancer Res"},{"key":"1670_CR26","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1007\/s10495-016-1228-3","volume":"21","author":"JM Shin","year":"2016","unstructured":"Shin JM, Jeong YJ, Cho HJ et al (2016) Suppression of c-Myc induces apoptosis via an AMPK\/mTOR-dependent pathway by 4-O-methyl-ascochlorin in leukemia cells. Apoptosis 21:657\u2013668. https:\/\/doi.org\/10.1007\/s10495-016-1228-3","journal-title":"Apoptosis"},{"key":"1670_CR27","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1111\/j.1365-2613.2006.00484.x","volume":"87","author":"G Ferns","year":"2006","unstructured":"Ferns G, Shams S, Shafi S (2006) Heat shock protein 27: its potential role in vascular disease. Int J Exp Pathol 87:253\u2013274","journal-title":"Int J Exp Pathol"},{"key":"1670_CR28","first-page":"4915","volume":"34","author":"L Belkacemi","year":"2014","unstructured":"Belkacemi L, Hebb MO (2014) HSP27 knockdown produces synergistic induction of apoptosis by HSP90 and kinase inhibitors in glioblastoma multiforme. Anticancer Res 34:4915\u20134927","journal-title":"Anticancer Res"},{"key":"1670_CR29","doi-asserted-by":"publisher","first-page":"4812","DOI":"10.1038\/sj.emboj.7601900","volume":"26","author":"CH Lee","year":"2007","unstructured":"Lee CH, Inoki K, Karbowniczek M et al (2007) Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J 26:4812\u20134823. https:\/\/doi.org\/10.1038\/sj.emboj.7601900","journal-title":"EMBO J"},{"key":"1670_CR30","doi-asserted-by":"publisher","first-page":"3376","DOI":"10.1111\/cas.13792","volume":"109","author":"S Yogosawa","year":"2018","unstructured":"Yogosawa S, Yoshida K (2018) Tumor suppressive role for kinases phosphorylating p53 in DNA damage-induced apoptosis. Cancer Sci 109:3376\u20133382","journal-title":"Cancer Sci"}],"container-title":["Apoptosis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10495-021-01670-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10495-021-01670-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10495-021-01670-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T08:12:08Z","timestamp":1623485528000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10495-021-01670-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,16]]},"references-count":30,"journal-issue":{"issue":"5-6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["1670"],"URL":"https:\/\/doi.org\/10.1007\/s10495-021-01670-4","relation":{},"ISSN":["1360-8185","1573-675X"],"issn-type":[{"value":"1360-8185","type":"print"},{"value":"1573-675X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,16]]},"assertion":[{"value":"4 April 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"LAM tissue samples were obtained from lung transplant donors for generation of cell lines, in accordance with the Declaration of Helsinki, approved by the Institutional Review Board at the University of Pennsylvania [] and provided by the National Disease Research Interchange (NDRI, Philadelphia, PA). LAM patients had given written informed consent and all the collected samples were treated anonymously. Paraffin embedded tissue samples were obtained retrospectively from the Departments of Pathology at Semmelweis University, Budapest, and from the University of Pecs, Pecs, Hungary and the National Koranyi Institute of Pulmonology, Budapest, Hungary. The study was approved by the Medical Research Council of Hungary (54034-4\/2018\/EKU).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}