title: Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner.
abstract: Bladder cancer (BC) is a common urologic tumor characterized by high risk of recurrence and mortality. Capsaicin (CPS), used as an intravesical drug for overactive bladder, was demonstrated to induce cell death in different cancer cells including BC cells.Here we found that treatment of high-grade BC cells with high dose of CPS triggers autophagy. Infact, the CPS treatment alters the redox homeostasis by inducing production of radicals, mitochondrial depolarization, alterations of ADP/ATP ratio and activation of AMPK pathway stimulating the autophagic process in BC cells. The inhibition of autophagy, by using the specific inhibitor bafilomycin A or Beclin 1 knock-down, enhanced the CPS-induced cell death, demonstrating that CPS-induced autophagy acts as a pro-survival process in BC cells. By using PCR arrays and FACS analysis, we found that the CPS-treated BC cells displayed typical mesenchymal features of the epithelial mesenchymal transition (EMT) as elongated shape and over-expression of vimentin, α5 and β1 integrin subunits, integrin-like kinase and the anti-apoptotic Bcl-2 proteins. Moreover, we demonstrated that CPS treatment stimulates upregulation of Dhh/Ptch2/Zeb2 members of the Hedgehog signaling pathway, increases CD24, VEGFA and TIMP1 and decreases CD44 and ALCAM mRNA expression levels. By PTCH2 knock-down we found that the Hedgehog signaling pathway is involved in the CPS-induced autophagy and EMT phenotype.Finally, we also showed that the CPS-resistant EMT-positive BC cells displayed an increased drug-resistance to the cytotoxic effects of mitomycin C, gemcitabine and doxorubicine drugs commonly used in BC therapy.
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.|Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Morelli
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.|Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cardinali
authors.affiliation: Department of Medical Oncology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Gismondi
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics; D002211:Capsaicin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000072082:Patched-2 Receptor / Q000235:genetics; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000093542:Gemcitabine
chemical_list: C491997:BECN1 protein, human; D000071186:Beclin-1; C509245:DHH protein, human; D053823:Hedgehog Proteins; C509246:IHH protein, human; C000606238:PTCH2 protein, human; D000072082:Patched-2 Receptor; D017382:Reactive Oxygen Species; C509239:SHH protein, human; D003841:Deoxycytidine; D016685:Mitomycin; D000244:Adenosine Diphosphate; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D002211:Capsaicin; D000093542:Gemcitabine
keywords: EMT; Hedgehog pathway; autophagy; bladder cancer; capsaicin