The Activation of PPARγ by (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic Acid Counteracts the Epithelial-Mesenchymal Transition Process in Skin Carcinogenesis

Enrica Flori; Sarah Mosca; Giorgia Cardinali; Stefania Briganti; Monica Ottaviani; Daniela Kovacs; Isabella Manni; Mauro Truglio; Arianna Mastrofrancesco; Marco Zaccarini; Carlo Cota; Giulia Piaggio; Mauro Picardo

doi:10.3390/cells12071007

The Activation of PPARγ by (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic Acid Counteracts the Epithelial-Mesenchymal Transition Process in Skin Carcinogenesis

Cells. 2023 Mar 24;12(7):1007. doi: 10.3390/cells12071007.

Affiliations

¹ Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy.
² SAFU Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Roma, Italy.
³ Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy.
⁴ Faculty of Medicine, Unicamillus International Medical University, 00131 Rome, Italy.

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the most common UV-induced keratinocyte-derived cancer, and its progression is characterized by the epithelial-mesenchymal transition (EMT) process. We previously demonstrated that PPARγ activation by 2,4,6-octatrienoic acid (Octa) prevents cutaneous UV damage. We investigated the possible role of the PPARγ activators Octa and the new compound (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic acid (A02) in targeting keratinocyte-derived skin cancer. Like Octa, A02 exerted a protective effect against UVB-induced oxidative stress and DNA damage in NHKs. In the squamous cell carcinoma A431 cells, A02 inhibited cell proliferation and increased differentiation markers' expression. Moreover, Octa and even more A02 counteracted the TGF-β1-dependent increase in mesenchymal markers, intracellular ROS, the activation of EMT-related signal transduction pathways, and cells' migratory capacity. Both compounds, especially A02, counterbalanced the TGF-β1-induced cell membrane lipid remodeling and the release of bioactive lipids involved in EMT. In vivo experiments on a murine model useful to study cell proliferation in adult animals showed the reduction of areas characterized by active cell proliferation in response to A02 topical treatment. In conclusion, targeting PPARγ may be useful for the prevention and treatment of keratinocyte-derived skin cancer.

Keywords: EMT; PPARγ; octatrienoic acid; skin carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Carcinoma, Squamous Cell* / pathology
Epithelial-Mesenchymal Transition
Mice
PPAR gamma / metabolism
Skin Neoplasms* / drug therapy
Skin Neoplasms* / metabolism
Transforming Growth Factor beta1 / pharmacology

Substances

Transforming Growth Factor beta1
PPAR gamma

Grants and funding

This study was partly supported by an unrestricted research grant provided by PPM Services SA-A Nogra Group Company (grant No. 17/09/G/29). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.