Oncotarget

Research Papers:

Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

Consuelo Amantini, Maria Beatrice Morelli, Massimo Nabissi, Claudio Cardinali, Matteo Santoni, Angela Gismondi and Giorgio Santoni _

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Oncotarget. 2016; 7:50180-50194. https://doi.org/10.18632/oncotarget.10326

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Abstract

Consuelo Amantini1, Maria Beatrice Morelli2,3, Massimo Nabissi2, Claudio Cardinali2,3, Matteo Santoni4, Angela Gismondi3, Giorgio Santoni2

1School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

2School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy

3Department of Molecular Medicine, Sapienza University, Rome, Italy

4Department of Medical Oncology, Polytechnic University of Marche, Ancona, Italy

Correspondence to:

Giorgio Santoni, email: giorgio.santoni@unicam.it

Keywords: capsaicin, bladder cancer, autophagy, EMT, Hedgehog pathway

Received: May 13, 2016     Accepted: June 13, 2016     Published: June 29, 2016

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.


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