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.

Targeting cancer stem cell pathways for cancer therapy

“…220 When the Hh ligand is present, it binds to PTCH, which changes the spatial conformation of PTCH, removing the inhibition of SMO activating the transcription factor GLI and inducing it to enter the cell nucleus, where GLI regulates cell growth, proliferation, and differentiation. 221 Studies have confirmed that abnormal activation of the Hh signaling pathway can be found in human cancers, 222 such as breast cancer, 223 lung cancer, 224 bladder cancer, 225 pancreatic cancer, 226 chondrosarcoma, 227 rhabdomyosarcoma, 228 neuroblastoma, 229 medulloblastoma, 230 and gastric cancer. 231 However, activation of Hh signaling is different in different tumors.…”

Capsaicin Induces Autophagy and Apoptosis in Human Nasopharyngeal Carcinoma Cells by Downregulating the PI3K/AKT/mTOR Pathway

“…It has been implicated in tumor growth and progression and explored as a potential therapeutic target [ 26 , 27 ]. Recently, a role for autophagy in capsaicin-induced cell death was proposed following reports indicating that capsaicin may induce autophagy, suggesting a promising therapeutic strategy for cancer [ 21 , 28 , 29 , 30 ]. However, only a few studies have examined capsaicin-induced apoptosis of NPC cells, and the effects of capsaicin on autophagic-associated pathways in NPC remain questionable.…”

Anti-Tumorigenic Effects of Capsaicin in Colon Cancer

“…High doses of capsaicin induce autophagy, apoptosis, and inhibition of autophagy sensitized capsaicin-induced apoptosis in bladder [41] and liver cancer cells [42]. Although the autophagic parameters were not measured in the current study, autophagy could be considered as a potential mechanism of capsaicin's anti-cancer activity in human colon cancer cells.…”