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

M. E. Pisanu, A. Noto, C. De Vitis, S. Morrone, G. Scognamiglio, G. Botti, F. Venuta, D. Diso, Z. Jakopin, F. Padula, A. Ricci, S. Mariotta, M. R. Giovagnoli, E. Giarnieri, I. Amelio, M. Agostini, G. Melino, G. Ciliberto, R. Mancini

Research output: Contribution to journalArticle

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 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.
Original languageEnglish
Pages (from-to)93-104
Number of pages12
JournalCancer Letters
Volume406
DOIs
Publication statusPublished - Oct 10 2017

Keywords

  • Adenocarcinoma/drug therapy/enzymology/pathology
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Biomarkers, Tumor/metabolism
  • Carcinoma, Non-Small-Cell Lung/drug therapy/enzymology/pathology
  • Carcinoma, Squamous Cell/drug therapy/enzymology/pathology
  • Case-Control Studies
  • Cell Proliferation/drug effects
  • Cisplatin/pharmacology
  • Drug Resistance, Neoplasm/drug effects
  • Drug Therapy, Combination
  • Endoplasmic Reticulum Stress/drug effects
  • Humans
  • Lung Neoplasms/drug therapy/enzymology/pathology
  • Neoplasm Staging
  • Neoplastic Stem Cells/drug effects/enzymology/pathology
  • Prognosis
  • Pyridazines/pharmacology
  • Stearoyl-CoA Desaturase/antagonists & inhibitors
  • Survival Rate
  • Thiadiazoles/pharmacology
  • Tumor Cells, Cultured
  • Cisplatin
  • Fatty acids
  • Lipid metabolism
  • Lung cancer stem cells
  • MF-438 inhibitor

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  • Cite this

    Pisanu, M. E., Noto, A., Vitis, C. D., Morrone, S., Scognamiglio, G., Botti, G., Venuta, F., Diso, D., Jakopin, Z., Padula, F., Ricci, A., Mariotta, S., Giovagnoli, M. R., Giarnieri, E., Amelio, I., Agostini, M., Melino, G., Ciliberto, G., & Mancini, R. (2017). Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. Cancer Letters, 406, 93-104. https://doi.org/S0304-3835(17)30463-9 [pii]