{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:35:51Z","timestamp":1790678151766,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T00:00:00Z","timestamp":1564358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR225"],"award-info":[{"award-number":["TRR225"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FOR2172"],"award-info":[{"award-number":["FOR2172"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BO1573"],"award-info":[{"award-number":["BO1573"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["AB"],"award-info":[{"award-number":["AB"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pigment Cell Melanoma Res"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acidosis of the tumor microenvironment is a characteristic of solid tumors such as malignant melanoma. Main causes of the extracellular acidification are metabolic alterations in cancer cells. While numerous studies showed that acidosis promotes tumor invasiveness, metastasis, and neoangiogenesis resulting in malignant progression, contrary data reported that acidosis induces cell apoptosis, inhibits cell proliferation, and mediates cell autophagy. Here, we show that low pH (pH 6.7) induces senescent\/quiescent phenotype in melanoma cells after long\u2010time treatment defined by induction of SA\u2010\u00df\u2010galactosidase, upregulation of p21, G<jats:sub>1<\/jats:sub>\/G<jats:sub>0<\/jats:sub> cell cycle arrest, and reduction of proliferation. Moreover, we revealed that extracellular acidosis triggers the inhibition of eIF2\u03b1 and subsequently the activation of ATF4 expression, a key component of the integrated stress response (ISR), indicating an acid\u2010mediated translation reprogramming. Interestingly, we also demonstrated that acidosis represses microphthalmia\u2010associated transcription factor (MITF) and activates the expression of the receptor tyrosine kinase AXL. This MITF<jats:sup>low<\/jats:sup>\/AXL<jats:sup>high<\/jats:sup> phenotype is correlated with drug resistance and therapeutic outcome in melanoma. Our results suggest that acidosis is an important microenvironmental factor triggering phenotypic plasticity and promoting tumor progression.<\/jats:p>","DOI":"10.1111\/pcmr.12811","type":"journal-article","created":{"date-parts":[[2019,7,16]],"date-time":"2019-07-16T13:10:29Z","timestamp":1563282629000},"page":"41-51","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Extracellular acidosis triggers a senescence\u2010like phenotype in human melanoma cells"],"prefix":"10.1111","volume":"33","author":[{"given":"Ines","family":"B\u00f6hme","sequence":"first","affiliation":[{"name":"Institute of Biochemistry, Department of Biochemistry and Molecular Medicine, Emil Fischer Center University of Erlangen\u2010N\u00fcrnberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8147-394X","authenticated-orcid":false,"given":"Anja","family":"Bosserhoff","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Department of Biochemistry and Molecular Medicine, Emil Fischer Center University of Erlangen\u2010N\u00fcrnberg Erlangen Germany"},{"name":"Comprehensive Cancer Center (CCC) Erlangen\u2010EMN Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0535"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2277"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.12495"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03841"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.406406"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/436642a"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/545838"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020278"},{"key":"e_1_2_8_10_1","first-page":"1","article-title":"Transcription factor ATF4 induces NLRP1 inflammasome expression during endoplasmic reticulum stress","volume":"10","author":"D'Osualdo A.","year":"2015","journal-title":"PLoS ONE"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3007"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.290940.116"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400495"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4RA15453C"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00866a011"},{"key":"e_1_2_8_16_1","first-page":"163","article-title":"Human melanoma cell line UV responses show independency of p53 function","volume":"10","author":"Haapajarvi T.","year":"1999","journal-title":"Cell Growth & Differentiation"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2008.00422.x"},{"key":"e_1_2_8_18_1","first-page":"1284","article-title":"Acid production in glycolysis\u2010impaired tumors provides new insights into tumor metabolism","volume":"8","author":"Helmlinger G.","year":"2002","journal-title":"Clinical Cancer Research"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfs130"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0424"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25879"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.71"},{"key":"e_1_2_8_23_1","first-page":"1","article-title":"Metabolic reprogramming in cancer cells: Glycolysis, glutaminolysis, and Bcl\u20102 proteins as novel therapeutic targets for cancer","volume":"14","author":"Li C.","year":"2016","journal-title":"World Journal of Surgical Oncology"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2017.08.031"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24226"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.339127"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00121214"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/35014006"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03890"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-008-9145-7"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6712"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2607"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1143"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/35018127"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2496-y"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-014-9506-4"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12518"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.05.003"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0983"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384101.2014.964107"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2017.08.010"},{"key":"e_1_2_8_42_1","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.4049\/jimmunol.151.5.2667","article-title":"IL\u20108 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor","volume":"151","author":"Schadendorf D.","year":"1993","journal-title":"The Journal of Immunology"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2016.1156264"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-397927-8.00011-7"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-2076"},{"key":"e_1_2_8_46_1","first-page":"4373","article-title":"Acid pH in tumors and its potential for therapeutic exploitation","volume":"49","author":"Tannock I. F.","year":"1989","journal-title":"Cancer Research"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0101053"},{"key":"e_1_2_8_48_1","first-page":"617","article-title":"Regulation of intracellular pH in human melanoma: Potential therapeutic implications","volume":"1","author":"Wahl M. L.","year":"2002","journal-title":"Molecular Cancer Therapeutics"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.124.3215.269"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.123.3191.309"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-8140(84)80077-8"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3881"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07203"}],"container-title":["Pigment Cell &amp; Melanoma Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pcmr.12811","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/pcmr.12811","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pcmr.12811","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T10:12:49Z","timestamp":1693995169000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/pcmr.12811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,29]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1]]}},"alternative-id":["10.1111\/pcmr.12811"],"URL":"https:\/\/doi.org\/10.1111\/pcmr.12811","archive":["Portico"],"relation":{},"ISSN":["1755-1471","1755-148X"],"issn-type":[{"value":"1755-1471","type":"print"},{"value":"1755-148X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,29]]},"assertion":[{"value":"2019-02-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}