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One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the \u03b3\u2010secretase inhibitor MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed its effects on autophagy. A dramatic, several fold increase of LC3B\u2010II\/LC3B\u2010I autophagy marker was noted on western blots, along with the emergence of punctate LC3B immunostaining in cultured cells. By combining the late stage autophagy inhibitor chloroquine (CQ) with MRK003, a significant induction in apoptosis and reduction in growth was noted as compared to Notch inhibition alone. A similar beneficial effect on inhibition of cloogenicity in soft agar was seen using the combination treatment. These results demonstrated that pharmacological Notch blockade can induce protective autophagy in glioma neurospheres, resulting in chemoresistance, which can be abrogated by combination treatment with autophagy inhibitors.<\/jats:p>","DOI":"10.1111\/bpa.12343","type":"journal-article","created":{"date-parts":[[2015,11,27]],"date-time":"2015-11-27T16:18:40Z","timestamp":1448641120000},"page":"713-723","source":"Crossref","is-referenced-by-count":46,"title":["Targeting Notch Signaling and Autophagy Increases Cytotoxicity in Glioblastoma Neurospheres"],"prefix":"10.1111","volume":"26","author":[{"given":"Manabu","family":"Natsumeda","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"},{"name":"Department of Neurosurgery Brain Research Institute, Niigata University Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Maitani","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Miyahara","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"},{"name":"Department of Oncology Tongji Hospital Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf D.","family":"Kahlert","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"},{"name":"Department of Neurosurgery University Medical Center D\u00fcsseldorf D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles G.","family":"Eberhart","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology Johns Hopkins Hospital Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,8]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28833"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/960803"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2119"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1590"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-013-0001-5"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/2051-5960-2-31"},{"key":"e_1_2_6_8_1","first-page":"2476","article-title":"Downregulation of Notch pathway by a gamma\u2010secretase inhibitor attenuates AKT\/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. 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