{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:47:28Z","timestamp":1783608448892,"version":"3.55.0"},"reference-count":71,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,12,26]],"date-time":"2018-12-26T00:00:00Z","timestamp":1545782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1 R21 CA208475-Terry D. Connell (PI); Patricia Masso-Welch (Co-I); Yasser Heakel (Co-I)"],"award-info":[{"award-number":["1 R21 CA208475-Terry D. Connell (PI); Patricia Masso-Welch (Co-I); Yasser Heakel (Co-I)"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"D'Youville School of Pharmacy","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Triple negative breast cancer (TNBC) remains a serious health problem with poor prognosis and limited therapeutic options. To discover novel approaches to treat TNBC, we screened cholera toxin (CT) and the members of the bacterial type II heat-labile enterotoxin family (LT-IIa, LT-IIb, and LT-IIc) for cytotoxicity in TNBC cells. Only LT-IIc significantly reduced viability of the TNBC cell lines BT549 and MDA-MB-231 (IC50 = 82.32 nM). LT-IIc had no significant cytotoxic effect on MCF10A (IC50 = 2600 nM), a non-tumorigenic breast epithelial cell line, and minimal effects on MCF7 and T47D, ER+ cells, or SKBR-3 cells, HER2+ cells. LT-IIc stimulated autophagy through inhibition of the mTOR pathway, while simultaneously inhibiting autophagic progression, as seen by accumulation of LC3B-II and p62. Morphologically, LT-IIc induced the formation of enlarged LAMP2+ autolysosomes, which was blocked by co-treatment with bafilomycin A1. LT-IIc induced apoptosis as demonstrated by the increase in caspase 3\/7 activity and Annexin V staining. Co-treatment with necrostatin-1, however, demonstrated that the lethal response of LT-IIc is elicited, in part, by concomitant induction of necroptosis. Knockdown of ATG-5 failed to rescue LT-IIc-induced cytotoxicity, suggesting LT-IIc can exert its cytotoxic effects downstream or independently of autophagophore initiation. Collectively, these experiments demonstrate that LT-IIc acts bifunctionally, inducing autophagy, while simultaneously blocking autolysosomal progression in TNBC cells, inducing a specific cytotoxicity in this breast cancer subtype.<\/jats:p>","DOI":"10.3390\/ijms20010085","type":"journal-article","created":{"date-parts":[[2018,12,26]],"date-time":"2018-12-26T11:31:21Z","timestamp":1545823881000},"page":"85","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["LT-IIc, A Bacterial Type II Heat-Labile Enterotoxin, Induces Specific Lethality in Triple Negative Breast Cancer Cells by Modulation of Autophagy and Induction of Apoptosis and Necroptosis"],"prefix":"10.3390","volume":"20","author":[{"given":"Patricia","family":"Masso-Welch","sequence":"first","affiliation":[{"name":"Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Girald Berlingeri","sequence":"additional","affiliation":[{"name":"Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA"},{"name":"Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D\u2019Youville College, 320 Porter Avenue, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie D.","family":"King-Lyons","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, Jacobs School of Medicine and Biomedical Sciences, The University at Buffalo, 955 Main Street, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorrie","family":"Mandell","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, Jacobs School of Medicine and Biomedical Sciences, The University at Buffalo, 955 Main Street, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, Jacobs School of Medicine and Biomedical Sciences, The University at Buffalo, 955 Main Street, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Greene","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, Jacobs School of Medicine and Biomedical Sciences, The University at Buffalo, 955 Main Street, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Federowicz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D\u2019Youville College, 320 Porter Avenue, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D\u2019Youville College, 320 Porter Avenue, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry D.","family":"Connell","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, Jacobs School of Medicine and Biomedical Sciences, The University at Buffalo, 955 Main Street, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser","family":"Heakal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D\u2019Youville College, 320 Porter Avenue, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nrclinonc.2016.66","article-title":"Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease","volume":"13","author":"Bianchini","year":"2016","journal-title":"Nat. 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