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Updated: Jul 7, 2025

Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
Targeting Fatty Acid Amide Hydrolase Counteracts the Epithelial-to-Mesenchymal Transition in Keratinocyte-Derived
Daniela Kovacs1, Enrica Flori1, Emanuela Bastonini1
1Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy.
Abstract:
The endocannabinoid system regulates physiological processes, and the modulation of endogenous endocannabinoid (eCB) levels is an attractive tool to contrast the development of pathological skin conditions including cancers. Inhibiting FAAH (fatty acid amide hydrolase), the degradation enzyme of the endocannabinoid anandamide (AEA) leads to the increase in AEA levels, thus enhancing its biological effects. Here, we evaluated the anticancer property of the FAAH inhibitor URB597, investigating its potential to counteract epithelial-to-mesenchymal transition (EMT), a process crucially involved in tumor progression. The effects of the compound were determined in primary human keratinocytes, ex vivo skin explants, and the squamous carcinoma cell line A431. Our results demonstrate that URB597 is able to hinder the EMT process by downregulating mesenchymal markers and reducing migratory potential. These effects are associated with the dampening of the AKT/STAT3 signal pathways and reduced release of pro-inflammatory cytokines and tumorigenic lipid species. The ability of URB597 to contrast the EMT process provides insight into effective approaches that may also include the use of FAAH inhibitors for the treatment of skin cancers.
Insights
The FAAH inhibitor URB597 can counteract skin cancer progression by inhibiting epithelial-to-mesenchymal transition (EMT). This research highlights its potential as a novel therapeutic strategy for skin cancers.
Area of Science:
- Dermatology
- Oncology
- Biochemistry
Background:
- The endocannabinoid system regulates physiological processes, and modulating its levels can impact skin pathologies.
- Elevated anandamide (AEA) levels, achieved by inhibiting fatty acid amide hydrolase (FAAH), show therapeutic potential.
- Epithelial-to-mesenchymal transition (EMT) is a critical process in skin tumor progression.
Purpose of the Study:
- To evaluate the anticancer properties of the FAAH inhibitor URB597.
- To investigate URB597's potential to counteract EMT in skin cancer models.
- To explore the molecular mechanisms underlying URB597's effects on EMT.
Main Methods:
- Treatment of primary human keratinocytes, ex vivo skin explants, and A431 squamous carcinoma cells with URB597.
- Assessment of EMT markers, cell migration, and signaling pathways (AKT/STAT3).
- Analysis of pro-inflammatory cytokines and lipid species release.
Main Results:
- URB597 effectively hindered the EMT process in tested models.
- Downregulation of mesenchymal markers and reduced migratory potential were observed.
- URB597 dampened AKT/STAT3 signaling and reduced pro-inflammatory and tumorigenic lipid release.
Conclusions:
- URB597 demonstrates significant potential in counteracting EMT, a key driver of skin cancer progression.
- FAAH inhibitors like URB597 represent a promising therapeutic avenue for skin cancer treatment.
- Targeting the endocannabinoid system offers novel strategies for managing skin malignancies.
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