Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line

Abstract

Fatty Acid Synthase (FASN) is responsible for the de novo synthesis of fatty acids, which are involved in the preservation of biological membrane structure, energy storage and assembly of factors involved in signal transduction. FASN plays a critical role in supporting tumor cell growth, thus representing a potential target for anti-cancer therapies. Moreover, this enzyme has been recently associated with increased PD-L1 expression, suggesting a role for fatty acids in the impairment of the immune response in the tumor microenvironment. Orlistat, a tetrahydrolipstatin used for the treatment of obesity, has been reported to reduce FASN activity, while inducing a sensible reduction of the growth potential in different cancer models. We have analyzed the effect of orlistat on different features involved in the tumor cell biology of the T-ALL Jurkat cell line. In particular, we have observed that orlistat inhibits Jurkat cell growth and induces a perturbation of cell cycle along with a decline of FASN activity and protein levels. Moreover, the drug produces a remarkable impairment of PD-L1 expression. These findings suggest that orlistat interferes with different mechanisms involved in the control of tumor cell growth and can potentially contribute to decrease the tumor-associated immune-pathogenesis.

Keywords:

• FASN
• leukemia
• PD-L1

Disclosure statement

The authors declare that they have no competing interests.

Author contributions

GC, AA, OF, MPF and EB conceived and designed the study and wrote the paper. GC, MZ, CV, OF, MPF, MN and MGC performed the experiments and analyzed the data, SC analyzed the data and performed statistical analysis. All authors reviewed the manuscript. In addition, all authors have read and approved the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Funding

This work was partially supported by the Funding of basic research activities 2017 from the Ministry of Education, University and Research (MIUR) to OF. SC is recipient of a fellowship from AIRC (Investigator Grant Project 17585).

Notes on contributors

Giorgia Cioccoloni

Giorgia Cioccoloni PhD. Research associate at the Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Expertise: clinical trials, in vivo and in vitro studies in cancer/obesity/nutrition.

Angelo Aquino

Angelo Aquino. Associate Professor of Pharmacology, School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Main area of interest: immunopharmacology of cancer.

Maria Notarnicola

Maria Notarnicola ScD. Board certified in Biochemistry, University of Bari, Italy. Main research activity: lipidome in metabolic diseases and cancer.

Maria Gabriella Caruso

Maria Gabriella Caruso MD. Board certified in Internal Medicine and Biochemistry, Head of the Ambulatory of Clinical Nutrition of the De Bellis Research Hospital, Castellana Grotte, Bari, Italy. Research activity interest: lipid metabolism in cancer.

Enzo Bonmassar

Enzo Bonmassar MD, PhD. Professor of Pharmacology and Research associate at the Consiglio Nazionale delle Ricerche (CNR, Italy). Main area of interest, role of Immunopharmacology in cancer treatment.

Manuela Zonfrillo

Manuela Zonfrillo. Graduate technician, National Research Council (Cnr, Rome Italy). Expertise: Cytometry, In vitro cell cultures.

Simona Caporali

Simona Caporali. Senior research assistant at the Istituto Dermopatico dell'Immacolata-IRCC. Expertise: molecular mechanisms involved in the pharmacological activity of anticancer drugs.

Cristina Villivà

Cristina Villivà. Scholarship holder, biologist specialized in nutrition sciences.

Maria Pia Fuggetta

Maria Pia Fuggetta. Senior researcher, National Research Council (Cnr, Rome Italy). Expertise: in vitro and in vivo studies in tumor and immunopharmacological field.

Ornella Franzese

Ornella Franzese PhD. Assistant Professor of Pharmacology, School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Main area of interest: Immunotherapy of cancer, immunosenescence and mechanism of T-cell exhaustion.