Inhibition of smoothened in breast cancer cells reduces CAXII expression and cell migration. Issue 12 (21st August 2018)

• Record Type: Journal Article
• Authors: Guerrini, Giuditta; Criscuoli, Mattia; Filippi, Irene; Naldini, Antonella; Carraro, Fabio
• Is Part Of: Journal of cellular physiology. Volume 233:Issue 12(2018:Dec.)
• Page Start: 9799
• Page End: 9811
• Publication Date: 2018-08-21
• Subjects: acetazolamide (AAZ) -- cyclopamine -- hypoxia -- interleukin‐1β (IL‐1β) -- sag dihydrochloride (SAG); Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.26947
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : Breast cancer (BC) relapse and metastasis are the leading cause of death and, together with drug resistance, keep mortality still high. The Hedgehog (Hh) pathway is expressed during embryogenesis, organogenesis and in adult tissue homeostasis and its aberrant activation is often associated with cancer. Carbonic anhydrase (CA) enzymes are important during development; they play a key role in controlling several cellular mechanisms, such as pH regulation, survival, and migration, and they are aberrantly expressed in cancer. The goal of this study was to investigate the interplay between the Hh pathway and CAXII in terms of BC cell migration. We here demonstrated that smoothened (SMO) silencing resulted in a reduction of CAXII expression at mRNA and protein level. This led to a decrease in cell migration, which was restored when cells were treated with an SMO agonist, Sag dihydrochloride (SAG), but not when cells were cotreated with SAG and the CAs inhibitor Acetazolamide. This suggested that the ability of SAG to promote cell migration was impaired when CAXII was inhibited. The reduction was also confirmed within hypoxic and inflammatory microenvironment, typical of BC, indicating a key role of the Hh pathway in controlling CAXII expression. Our results may contribute to further understand the physiology of BC cells and indicate that the Hh pathway controls BC cell migration and cell invasion also through CAXII, with important implications in identifying novel therapeutic targets. Abstract : We here demonstrated that Smoothened (SMO) silencing resulted in a reduction of CAXII expression at messenger RNA (mRNA) and protein level in breast cancer (BC) cell lines. This led to a decrease in cell migration, which was restored when cells were treated with a SMO agonist. The reduction was confirmed also within hypoxic and inflammatory microenvironment, typical of BC, indicating a key role of the Hedgehog (Hh) pathway in controlling CAXII expression. Our results indicate that the Hh pathway controls BC cell migration and cell invasion through CAXII, with important implications in identifying novel therapeutic targets.