{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:58:20Z","timestamp":1772164700092,"version":"3.50.1"},"reference-count":50,"publisher":"American Association for Cancer Research (AACR)","issue":"5","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sonic hedgehog (SHh) signaling is important in the pathogenesis of various human cancers, such as medulloblastomas, and it has been identified as a valid target for anticancer therapeutics. The SHh inhibitor cyclopamine induces apoptosis. The bioactive sphingolipid ceramide mediates cell death in response to various chemotherapeutic agents; however, ceramide's roles\/mechanisms in cyclopamine-induced apoptosis are unknown. Here, we report that cyclopamine mediates ceramide generation selectively via induction of neutral sphingomyelin phosphodiesterase 3, SMPD3 (nSMase2) in Daoy human medulloblastoma cells. Importantly, short interfering RNA-mediated knockdown of nSMase2 prevented cyclopamine-induced ceramide generation and protected Daoy cells from drug-induced apoptosis. Accordingly, ectopic wild-type N-SMase2 caused cell death, compared with controls, which express the catalytically inactive N-SMase2 mutant. Interestingly, knockdown of smoothened (Smo), a target protein for cyclopamine, or Gli1, a downstream signaling transcription factor of Smo, did not affect nSMase2. Mechanistically, our data showed that cyclopamine induced nSMase2 and cell death selectively via increased nitric oxide (NO) generation by neuronal-nitric oxide synthase (n-NOS) induction, in Daoy medulloblastoma, and multiple other human cancer cell lines. Knockdown of n-NOS prevented nSMase2 induction and cell death in response to cyclopamine. Accordingly, N-SMase2 activity-deficient skin fibroblasts isolated from homozygous fro\/fro (fragilitas ossium) mice exhibited resistance to NO-induced cell death. Thus, our data suggest a novel off-target function of cyclopamine in inducing apoptosis, at least in part, by n-NOS\/NO-dependent induction of N-SMase2\/ceramide axis, independent of Smo\/Gli inhibition. Mol Cancer Ther; 11(5); 1092\u2013102. \u00a92012 AACR.<\/jats:p>","DOI":"10.1158\/1535-7163.mct-11-0705","type":"journal-article","created":{"date-parts":[[2012,3,27]],"date-time":"2012-03-27T22:34:07Z","timestamp":1332887647000},"page":"1092-1102","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Off-Target Function of the Sonic Hedgehog Inhibitor Cyclopamine in Mediating Apoptosis via Nitric Oxide\u2013Dependent Neutral Sphingomyelinase 2\/Ceramide Induction"],"prefix":"10.1158","volume":"11","author":[{"given":"Marisa","family":"Meyers-Needham","sequence":"first","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Jocelyn A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Salih","family":"Gencer","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"R. David","family":"Sentelle","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Sahar A.","family":"Saddoughi","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Christopher J.","family":"Clarke","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Yusuf A.","family":"Hannun","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Haakan","family":"Norell","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Telma Martins","family":"da Palma","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Michael","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Jacqueline M.","family":"Kraveka","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Zohreh","family":"Khavandgar","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Monzur","family":"Murshed","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"M. Ozgur","family":"Cevik","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]},{"given":"Besim","family":"Ogretmen","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"},{"name":"Authors' Affiliations:\u20081Department of Biochemistry and Molecular Biology, 2Hollings Cancer Center, 3Department of Pediatrics, Division of Pediatric Oncology, and 4Department of Surgery, Medical University of South Carolina, Charleston, South Carolina; and 5Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}]}],"member":"1086","published-online":{"date-parts":[[2012,5,8]]},"reference":[{"key":"2022060800100079600_bib1","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/35077219","article-title":"The Hedgehog and Wnt signalling pathways in cancer","volume":"411","author":"Taipale","year":"2001","journal-title":"Nature"},{"key":"2022060800100079600_bib2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrclinonc.2010.196","article-title":"Targeting cancer stem cells by 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