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

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Stearoyl-CoA Desaturase
Neoplastic Stem Cells
Cisplatin
Lung Neoplasms
Up-Regulation
Monounsaturated Fatty Acids
Endoplasmic Reticulum Stress
Autophagy
beta Catenin
Therapeutics
Cell Culture Techniques
Apoptosis
Recurrence
Drug Therapy
Enzymes
Neoplasms

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

Cite this

Pisanu, M. E., Noto, A., Vitis, C. D., Morrone, S., Scognamiglio, G., Botti, 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]

Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. / Pisanu, M. E.; Noto, A.; Vitis, C. De; 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.

In: Cancer Letters, Vol. 406, 10.10.2017, p. 93-104.

Research output: Contribution to journalArticle

Pisanu, ME, Noto, A, Vitis, CD, Morrone, S, Scognamiglio, G, Botti, G, Venuta, F, Diso, D, Jakopin, Z, Padula, F, Ricci, A, Mariotta, S, Giovagnoli, MR, 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, vol. 406, pp. 93-104. https://doi.org/S0304-3835(17)30463-9 [pii]
Pisanu, M. E. ; Noto, A. ; Vitis, C. De ; 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. / Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. In: Cancer Letters. 2017 ; Vol. 406. pp. 93-104.
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T1 - Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells

AU - Pisanu, M. E.

AU - Noto, A.

AU - Vitis, C. De

AU - Morrone, S.

AU - Scognamiglio, G.

AU - Botti, G.

AU - Venuta, F.

AU - Diso, D.

AU - Jakopin, Z.

AU - Padula, F.

AU - Ricci, A.

AU - Mariotta, S.

AU - Giovagnoli, M. R.

AU - Giarnieri, E.

AU - Amelio, I.

AU - Agostini, M.

AU - Melino, G.

AU - Ciliberto, G.

AU - Mancini, R.

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N2 - 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.

AB - 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.

KW - Adenocarcinoma/drug therapy/enzymology/pathology

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis/drug effects

KW - Biomarkers, Tumor/metabolism

KW - Carcinoma, Non-Small-Cell Lung/drug therapy/enzymology/pathology

KW - Carcinoma, Squamous Cell/drug therapy/enzymology/pathology

KW - Case-Control Studies

KW - Cell Proliferation/drug effects

KW - Cisplatin/pharmacology

KW - Drug Resistance, Neoplasm/drug effects

KW - Drug Therapy, Combination

KW - Endoplasmic Reticulum Stress/drug effects

KW - Humans

KW - Lung Neoplasms/drug therapy/enzymology/pathology

KW - Neoplasm Staging

KW - Neoplastic Stem Cells/drug effects/enzymology/pathology

KW - Prognosis

KW - Pyridazines/pharmacology

KW - Stearoyl-CoA Desaturase/antagonists & inhibitors

KW - Survival Rate

KW - Thiadiazoles/pharmacology

KW - Tumor Cells, Cultured

KW - Cisplatin

KW - Fatty acids

KW - Lipid metabolism

KW - Lung cancer stem cells

KW - MF-438 inhibitor

U2 - S0304-3835(17)30463-9 [pii]

DO - S0304-3835(17)30463-9 [pii]

M3 - Article

VL - 406

SP - 93

EP - 104

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -