title: Cantharidin Induces Apoptosis Through the Calcium/PKC-Regulated Endoplasmic Reticulum Stress Pathway in Human Bladder Cancer Cells.
abstract: Bladder cancer is a common malignancy worldwide. However, there is still no effective therapy for bladder cancer. In this study, we investigated the cytotoxic effects of cantharidin [a natural toxin produced (pure compound) from Chinese blister beetles (Mylabrisphalerata or Mylabriscichorii) and Spanish flies (Cantharis vesicatoria)] in human bladder cancer cell lines (including: T24 and RT4 cells). Treatment of human bladder cancer cells with cantharidin significantly decreased cell viability. The increase in the expressions of caspase-3 activity and cleaved form of caspase-9/-7/-3 were also increased in cantharidin-treated T24 cells. Furthermore, cantharidin increased the levels of phospho-eIF2α and Grp78 and decreased the protein expression of procaspase-12, which was accompanied by the increase in calpain activity in T24 cells. Cantharidin was capable of increasing the intracellular Ca (2+) and the phosphorylation of protein kinase C (PKC) in T24 cells. The addition of BAPTA/AM (a Ca (2+) chelator) and RO320432 (a selective cell-permeable PKC inhibitor) effectively reversed the increase in caspase-3 and calpain activity, the phosphorylation levels of PKC and eIF2α and Grp78 protein expression, and the decrease in procaspase-12 expression induced by cantharidin. Importantly, cantharidin significantly decreased the tumor volume (a dramatic 71% reduction after 21 days of treatment) in nude mice xenografted with T24 cells. Taken together, these results indicate cantharidin induced human bladder cancer cell apoptosis through a calcium/PKC-regulated ER stress pathway. These findings suggest that cantharidin may be a novel and potential anticancer agent targeting on bladder cancer cells.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan , Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County, Taiwan.
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Su
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.forename: Kuan-I
authors.initials: KI
authors.lastname: Lee
authors.forename: Kou-Tong
authors.initials: KT
authors.lastname: Huang
authors.forename: Tien-Hui
authors.initials: TH
authors.lastname: Lu
authors.forename: Kai-Min
authors.initials: KM
authors.lastname: Fang
authors.forename: Chin-Ching
authors.initials: CC
authors.lastname: Wu
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yen
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Su
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000502:physiology; D002193:Cantharidin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010212:Papilloma / Q000235:genetics* / Q000473:pathology; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D011493:Protein Kinase C; D053148:Caspase 3; D002193:Cantharidin; D002118:Calcium
keywords: Bladder Cancer Cells; Calcium; Cantharidin; ER Stress; PKC