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Cancer Lett. 2017 Oct 10;406:93-104. doi: 10.1016/j.canlet.2017.07.027. Epub 2017 Aug 7.

Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells.

Author information

1
Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
2
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
3
Experimental Pharmacology Unit, National Cancer Institute, Fondazione "G. Pascale" - IRCCS, 80131 Naples, Italy.
4
Director Dept. Pathology National Cancer Institute, Fondazione "G. Pascale" - IRCCS, 80131 Naples, Italy.
5
Department of Surgical Sciences and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, 00161 Rome, Italy.
6
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
7
Section of Histology and Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 00161 Rome, Italy.
8
Medical Research Council, Toxicology Unit, Leicester University, Hodgkin Building, LE1 9HN Leicester, UK.
9
Medical Research Council, Toxicology Unit, Leicester University, Hodgkin Building, LE1 9HN Leicester, UK; Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133 Rome, Italy.
10
Scientific Directorate, IRCSS Regina Elena National Cancer Institute, 00128 Rome, Italy.
11
Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy. Electronic address: rita.mancini@uniroma1.it.

Abstract

Poor prognosis in lung cancer has been attributed to the presence of lung cancer stem cells (CSCs) which resist chemotherapy and cause disease recurrence. Hence, the strong need to identify mechanisms of chemoresistance and to develop new combination therapies. We have previously shown that Stearoyl-CoA-desaturase 1 (SCD1), the enzyme responsible for the conversion of saturated to monounsaturated fatty acids is upregulated in 3D lung cancer spheroids and is an upstream activator of key proliferation pathways β-catenin and YAP/TAZ. Here we first show that SCD1 expression, either alone or in combination with a variety of CSCs markers, correlates with poor prognosis in adenocarcinoma (ADC) of the lung. Treatment of lung ADC cell cultures with cisplatin enhances the formation of larger 3D tumor spheroids and upregulates CSCs markers. In contrast, co-treatment with cisplatin and the SCD1 inhibitor MF-438 reverts upregulation of CSCs markers, strongly synergizes in the inhibition of 3D spheroids formation and induces CSCs apoptosis. Mechanistically, SCD1 inhibition activates endoplasmic reticulum stress response and enhances autophagy. These data all together support the use of combination therapy with SCD1 inhibitors to achieve better control of lung cancer.

KEYWORDS:

Cisplatin; Fatty acids; Lipid metabolism; Lung cancer stem cells; MF-438 inhibitor

PMID:
28797843
DOI:
10.1016/j.canlet.2017.07.027
[Indexed for MEDLINE]

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