{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T23:42:46Z","timestamp":1785195766002,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T00:00:00Z","timestamp":1694044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"publisher","award":["0604456551"],"award-info":[{"award-number":["0604456551"]}],"id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Metastatic (as well as tumor) microenvironments contain both cancer\u2010promoting and cancer\u2010restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung\u2010derived antimetastatic factor. In the present study, exploring mechanisms regulating melanoma brain metastasis, we discovered that brain\u2010derived factors restrain proliferation and induce apoptosis and necrosis of brain\u2010metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that perform these antimetastatic functions. Neither the alpha nor the beta subunit alone was inhibitory. An alpha\/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer\u2010induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer\u2010treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and\u00a0IRS2 proteins, playing crucial roles in cancer cell sustainability and progression. Thus, we hypothesize that the hemoglobin dimer functions as a resistance factor against brain\u2010metastasizing cancer cells.<\/jats:p>","DOI":"10.1002\/ijc.34702","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T12:17:20Z","timestamp":1694089040000},"page":"561-572","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A heterodimer of \u03b1 and \u03b2 hemoglobin chains functions as an innate anticancer agent"],"prefix":"10.1002","volume":"154","author":[{"given":"Maharrish","family":"Chelladurai","sequence":"first","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Human Virology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivan","family":"Izraely","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shlomit","family":"Ben\u2010Menachem","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Bengaiev","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orit","family":"Sagi\u2010Assif","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weirong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Institute of Human Virology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metsada","family":"Pasmanik Chor","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, The George S. Wise Faculty of Life Science Tel Aviv University  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-3683","authenticated-orcid":false,"given":"Dave S.","family":"Hoon","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Medicine and Sequencing Center Saint John's Cancer Institute at Providence Saint John's Health Center  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuyuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Human Virology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0341-4343","authenticated-orcid":false,"given":"Isaac P.","family":"Witz","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33247"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-2917"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-3962"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00280-x"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0965-7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw168"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3394"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.850856"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(06)98001-4"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2328"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2929"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa285"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm-21-3665"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31745"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4509"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-018-9891-0"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12111513"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19018"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27324"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28255"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.877380"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(08)01606-6"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123845"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415X19500447"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.238"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.3951"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-021-01424-5"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3385"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.2174\/18715281113126660060"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.bor.0000381996.69261.71"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1183442"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2021.145429"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6261721"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.867013"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-021-00422-9"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.643291"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2017.02.001"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/847383"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.835843"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.114008"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01320"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2016.05.025"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2014.12.005"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.701975"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-030620-102906"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2020.108406"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104855"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1566120"},{"key":"e_1_2_11_50_1","article-title":"Regulation and role of neuron\u2010derived hemoglobin in the mouse hippocampus","volume":"23","author":"Lu Y","year":"2022","journal-title":"Int J Mol Sci"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813216106"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22062"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-022-00445-6"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.10.031"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12872"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071683"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA119.001886"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.34702","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T11:34:41Z","timestamp":1703763281000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.34702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,7]]},"references-count":56,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,2]]}},"alternative-id":["10.1002\/ijc.34702"],"URL":"https:\/\/doi.org\/10.1002\/ijc.34702","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,7]]},"assertion":[{"value":"2023-02-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}