{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:47:19Z","timestamp":1789908439580,"version":"4.0.1"},"reference-count":24,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The main function of folate receptor \u03b1 (FOLR\u03b1) has been considered to mediate intracellular folate uptake and induce tumor cell proliferation. Given the broad spectrum of expression among malignant tumors, including gastric cancer (GC) but not in normal tissue, FOLR\u03b1 represents an attractive target for tumor\u2010selective drug delivery. However, the efficacy of anti\u2010FOLR\u03b1 monoclonal antibodies (mAbs) has not been proved so far, with the reason for this failure remaining unclear, raising the need for a better understanding of FOLR\u03b1 function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The distribution of FOLR\u03b1 in GC cells was evaluated by immunohistochemistry. The impacts of FOLR\u03b1 expression on the survival of GC patients and GC cell lines were examined with the Gene Expression Omnibus database and by siRNA of FOLR\u03b1. RNA\u2010sequencing and Microarray analysis was conducted to identify the function of FOLR\u03b1. Proteins that interact with FOLR\u03b1 were identified with shotgun LC\u2010MS\/MS. The antitumor efficacy of the anti\u2010FOLR\u03b1 mAb farletuzumab as well as the antibody\u2010drug conjugate (ADC) consists of the farletuzumab and the tublin\u2010depolymerizing agent eribulin (MORAb\u2010202) was evaluated both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>FOLR\u03b1 was detected both at the cell membrane and in the cytoplasm. Shorter overall survival was associated with FOLR\u03b1 expression in GC patients, whereas reduction of FOLR\u03b1 attenuated cell proliferation without inducing cell death in GC cell lines. Transcriptomic and proteomic examinations revealed that the FOLR\u03b1\u2010expressing cancer cells possess a mechanism of chemotherapy resistance supported by MDM2, and FOLR\u03b1 indirectly regulates it through a chaperone protein prohibitin2 (PHB2). Although reduction of FOLR\u03b1 brought about vulnerability for oxaliplatin by diminishing MDM2 expression, farletuzumab did not suppress the MDM2\u2010mediated chemoresistance and cell proliferation in GC cells. On the other hand, MORAb\u2010202 showed significant antitumor efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLR\u03b1\u2010expressing tumor.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.454","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T22:34:45Z","timestamp":1622586885000},"source":"Crossref","is-referenced-by-count":20,"title":["Folate receptor \u03b1 increases chemotherapy resistance through stabilizing MDM2 in cooperation with PHB2 that is overcome by MORAb\u2010202 in gastric cancer"],"prefix":"10.1002","volume":"11","author":[{"given":"Hitomi","family":"Sakai","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Kindai University Faculty of Medicine  Osaka\u2010Sayama Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-4850","authenticated-orcid":false,"given":"Hisato","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Kindai University Faculty of Medicine  Osaka\u2010Sayama Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Teramura","sequence":"additional","affiliation":[{"name":"Division of Cell Biology for Regenerative Medicine Institute of Advanced Clinical Medicine Kindai University Faculty of Medicine  Osaka\u2010Sayama Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0152-6560","authenticated-orcid":false,"given":"Yuta","family":"Onodera","sequence":"additional","affiliation":[{"name":"Division of Cell Biology for Regenerative Medicine Institute of Advanced Clinical Medicine Kindai University Faculty of Medicine  Osaka\u2010Sayama Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Somers","sequence":"additional","affiliation":[{"name":"AD Franchise Special Mission, Eisai Inc.  Woodcliff Lake New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Furuuchi","sequence":"additional","affiliation":[{"name":"Epochal Precision Anti\u2010Cancer Therapeutics (EPAT), Eisai Inc.  Exton Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Uenaka","sequence":"additional","affiliation":[{"name":"Epochal Precision Anti\u2010Cancer Therapeutics (EPAT), Eisai Inc.  Exton Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoji","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Kindai University Faculty of Medicine  Osaka\u2010Sayama Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Kindai University Faculty of Medicine  Osaka\u2010Sayama Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12327"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2004.12.026"},{"key":"e_1_2_12_5_1","first-page":"020","article-title":"Exploiting the folate receptor \u03b1 in 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