{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:27:01Z","timestamp":1792132021960,"version":"4.4.0"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T00:00:00Z","timestamp":1599696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology","award":["NRF-2018R1D1A1B07050517"],"award-info":[{"award-number":["NRF-2018R1D1A1B07050517"]}]},{"name":"Seoul National University Bundang Hospital Research Fund","award":["02-2018-010"],"award-info":[{"award-number":["02-2018-010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nuclear factor kappa B (NF-\u03baB) activation is a well-known mechanism by which chemoresistance to anticancer agents is reported. It is well-known that irinotecan as a chemotherapeutic drug against non-small-cell lung carcinoma (NSCLC) has limited anticancer effect due to NF-\u03baB activation. In this study, we propose the novel role of GRA16, a dense granule protein of Toxoplasma gondii, as an anticancer agent to increase the effectiveness of chemotherapy via the inhibition of NF-\u03baB activation. To demonstrate this, H1299 cells were stably transfected with GRA16. The anticancer effects of GRA16 were demonstrated as a reduction in tumor size in a mouse xenograft model. GRA16 directly elevated B55 regulatory subunit of protein phosphatase 2A (PP2A-B55) expression in tumor cells, thereby decreasing GWL protein levels and ENSA phosphorylation. This cascade, in turn, induced PP2A-B55 activation and suppressed AKT\/ERK phosphorylation and cyclin B1 levels, suggesting reduced cell survival and arrested cell cycle. Moreover, PP2A-B55 activation and AKT phosphorylation inhibition led to NF-\u03baB inactivation via the reduction in inhibitory kappa B kinase beta (IKK\u03b2) levels, de-phosphorylation of inhibitor of kappa B alpha (I\u03baB\u03b1), and reduction in the nuclear transit of NF-\u03baB p65. Furthermore, this molecular mechanism was examined under irinotecan treatment. The PP2A-B55\/AKT\/NF-\u03baB p65 pathway-mediated anticancer effects were only induced in the presence of GRA16, but not in the presence of irinotecan. Moreover, GRA16 synergistically promoted the anticancer effects of irinotecan via the induction of the sub-G1 phase and reduction of cell proliferation. Collectively, irinotecan and GRA16 co-treatment promotes the anticancer effects of irinotecan via NF-\u03baB inhibition and cell cycle arrest induced by GRA16, subsequently increasing the chemotherapeutic effect of irinotecan to NSCLC cells via NF-\u03baB inhibition.<\/jats:p>","DOI":"10.3390\/ijms21186642","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T22:58:01Z","timestamp":1599778681000},"page":"6642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Toxoplasma GRA16 Inhibits NF-\u03baB Activation through PP2A-B55 Upregulation in Non-Small-Cell Lung Carcinoma Cells"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-1966","authenticated-orcid":false,"given":"Seung-Hwan","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Gyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hun","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do-Won","family":"Ham","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1215-1079","authenticated-orcid":false,"given":"Eun-Hee","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"},{"name":"Seoul National University Bundang Hospital, Seongnam 13620, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.lungcan.2010.08.022","article-title":"Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC","volume":"71","author":"Chang","year":"2011","journal-title":"Lung Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"583929","DOI":"10.1155\/2011\/583929","article-title":"TP53 mutations in nonsmall cell lung cancer","volume":"2011","author":"Mogi","year":"2011","journal-title":"BioMed Res. 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