期刊
CANCER LETTERS
卷 406, 期 -, 页码 93-104出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.07.027
关键词
Cisplatin; MF-438 inhibitor; Lipid metabolism; Lung cancer stem cells; Fatty acids
类别
资金
- Italian Association for Cancer Research (AIRC) [IG17009, IG15216]
- Fondo di Ricerca di Ateneo [C26A142LZ8]
- POR FESR Lazio
- Fondazione Veronesi fellowship
- Medical Research Council [MC_U132670600] Funding Source: researchfish
- MRC [MC_U132670600] Funding Source: UKRI
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 beta-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. (C) 2017 Elsevier B.V. All rights reserved.
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