title: Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib.
abstract: Increasing evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth, and are hypothesized to account for therapeutic resistance. Based on the expression of the surface markers CD44, CD24, and EPCAM, putative CSCs have also been identified in pancreatic cancers. It has been well established that aberrant activation of β-catenin signaling pathway may contribute to the maintenance of CSCs. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. In our previous studies, we demonstrated that cantharidin treatment induced phosphorylation of β-catenin, leading to repression on β-catenin pathway. Therefore, in the present study, we investigated whether cantharidin and its derivant, norcantharidin, could repress the stemness of pancreatic cancer cells through repression on β-catenin pathway. By using microarray and flow cytometry, we found that treatment with cantharidin and norcantharidin repressed the expression of CD44, CD24, and EPCAM at both mRNA and protein levels, leading to decreased CD44(+)/CD24(+)/EPCAM(+) proportion, the putative pancreatic CSC subset. Pretreatment with the β-catenin pathway inhibitor FH535, attenuated the cantharidin- and norcantharidin-induced repression on CD44, CD24, and EPCAM, suggesting cantharidin and its derivant repressed stemness of pancreatic cancer cells in β-catenin pathway-dependent manner. Furthermore, cantharidin and norcantharidin strengthened the cytotoxicity of gemcitabine and erlotinib, two well established pharmacotherapeutics against pancreatic cancers, indicating cantharidin and norcantharidin could be promising candidates for reversing drug resistance in pancreatic cancers. In conclusion, we presently propose that cantharidin and norcantharidin hold their promise in pancreatic cancer therapy through repression on stemness and strengthening the cytotoxicity of the present therapeutics.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Meng-Yao
authors.initials: MY
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Zhi
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Ze-Yi
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Fei-Ran
authors.initials: FR
authors.lastname: Gong
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D002193:Cantharidin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D051176:beta Catenin; D003841:Deoxycytidine; C069741:norcantharidin; D000069347:Erlotinib Hydrochloride; D002193:Cantharidin; D000093542:Gemcitabine