{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T13:03:54Z","timestamp":1779714234775,"version":"3.53.1"},"reference-count":41,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>In nasopharyngeal carcinoma, mitochondria often function abnormally. However, the precise signals that cause excessive mitochondrial division are still undefined. Levels of the neuropeptide Vasoactive Intestinal Peptide are altered in NPC tissues. How VIP influences the metabolic behavior of cancer cells is not well established. Our experiments utilized established NPC cell lines. We tested how physiological concentrations (10\u2013100\u2009nM) of VIP exposure affect survival and mitochondrial integrity. Morphology was analyzed using fluorescence staining. We measured functional outputs, including reactive oxygen species, ATP levels, and membrane potential. Immunoblotting and activity assays helped trace the involved molecular events. Both genetic knockdown and a highly selective pharmacological inhibitor confirmed the proposed mechanism. To address pathway generality, experiments were repeated in an additional NPC line (NPC\u2011TW02). Receptor identity was probed using siRNA against VPAC1 and VPAC2. Selectivity for cancer cells was tested in normal nasopharyngeal epithelial NP69 cells. Administering VIP at 10\u2013100\u2009nM increased oxidative stress within mitochondria in a concentration\u2010dependent manner. The transmembrane potential collapsed. Activity of the electron transport chain's Complex IV was suppressed, and cellular ATP content diminished. These failures led to pronounced mitochondrial fragmentation. VIP treatment (100\u2009nM) rapidly activated the kinase PKC\u03b4. PKC\u03b4 then phosphorylated the fission protein Drp1 at serine 616, causing Drp1 to accumulate at mitochondria. When we applied the compound Rottlerin to inhibit PKC\u03b4, it effectively blocked Drp1 modification and recruitment. Consequently, mitochondrial fragmentation was prevented and energy metabolism recovered. These findings were confirmed in NPC\u2011TW02 cells. VPAC1 silencing, but not VPAC2 silencing, blocked VIP effects in C666\u20101 cells. Normal NP69 cells showed no significant response to VIP under the tested conditions. This work defines a previously unrecognized VIP\u2010PKC\u03b4\u2010Drp1 pathway that operates at physiologically relevant VIP concentrations and controls mitochondrial division and fitness in NPC cells. This signaling axis highlights a specific metabolic weak point in these tumors. Our results suggest PKC\u03b4 could be investigated as a candidate target for therapies designed to correct mitochondrial dysfunction in nasopharyngeal carcinoma.<\/jats:p>","DOI":"10.1002\/ddr.70287","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T06:30:26Z","timestamp":1776666626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PKC\u03b4\u2010Drp1 Axis Mediates VIP\u2010Induced Mitochondrial Fragmentation and Metabolic Crisis in Nasopharyngeal Carcinoma"],"prefix":"10.1002","volume":"87","author":[{"given":"Jingda","family":"Xu","sequence":"first","affiliation":[{"name":"Faculty of Chinese Medicine Macau University of Science and Technology, Estrada do Istmo Taipa Macau China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanzheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine Zhuhai City Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7814-6878","authenticated-orcid":false,"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine Macau University of Science and Technology, Estrada do Istmo Taipa Macau China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine Zhuhai City Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011072"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808249105"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C700083200"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30956-0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7401062"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2012.01.004"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.56.2.7"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-4497"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.1199"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.01871.x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2014.06.021"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.01.002"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2019.101890"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00001.2014"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201511036"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3871"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000218"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.10.4345"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-3835(97)81762-4"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00257.2009"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.05.020"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.7.2.5256"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E10-06-0551"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2025.114731"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06946.x"},{"issue":"11","key":"e_1_2_9_28_1","first-page":"3105","article-title":"Vasoactive Intestinal Peptide\/Pituitary Adenylate Cyclase\u2010Activating Peptide Receptor Subtypes in Human Tumors and Their Tissues of Origin","volume":"60","author":"Reubi J. 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