Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis

Mariachiara Buccarelli, Matteo Marconi, Simone Pacioni, Ivana De Pascalis, Quintino Giorgio D'Alessandris, Maurizio Martini, Barbara Ascione, Walter Malorni, Luigi Maria Larocca, Roberto Pallini, Lucia Ricci-Vitiani, Paola Matarrese

Research output: Contribution to journalArticle

Abstract

The role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle progression, de facto exerting a cytostatic activity. Hence, it represents an important target for anticancer therapy. For example, temozolomide (TMZ), of use for glioblastoma (GBM) treatment, appears as capable of inducing autophagy partially inhibiting cancer cell proliferation. However, GBM, a very aggressive brain tumor with poor prognosis even after surgery and radio-chemotherapy, invariably recurs and leads to patient death. Since cancer stem cells have been hypothesized to play a role in refractory/relapsing cancers, in the present work we investigated if autophagy could represent a constitutive cytoprotection mechanism for glioblastoma stem-like cells (GSCs) and if the modulation of autophagic process could affect GBM growth and survival. Thus, in the present study we first evaluated the relevance of autophagy in GBM tumor specimens, then its occurrence in GSCs and, finally, if modulation of autophagy could influence GSC response to TMZ. Our results suggested that, in vitro, the impairing autophagic process with quinacrine, a compound able to cross the blood-brain barrier, increased GSC susceptibility to TMZ. Death of GSCs was apparently due to the iron dependent form of programmed cell death characterized by the accumulation of lipid peroxides called ferroptosis. These results underscore the relevance of the modulation of autophagy in the GSC survival and death and suggest that triggering of ferroptosis in GSCs could represent a novel and important target for the management of glioblastoma.

Original languageEnglish
Pages (from-to)841
JournalCell death & disease
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 6 2018

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temozolomide
Autophagy
Glioblastoma
Stem Cells
Cell Death
Neoplasms

Keywords

  • Autophagy
  • cancer
  • Glioblastoma

Cite this

Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. / Buccarelli, Mariachiara; Marconi, Matteo; Pacioni, Simone; De Pascalis, Ivana; D'Alessandris, Quintino Giorgio; Martini, Maurizio; Ascione, Barbara; Malorni, Walter; Larocca, Luigi Maria; Pallini, Roberto; Ricci-Vitiani, Lucia; Matarrese, Paola.

In: Cell death & disease, Vol. 9, No. 8, 06.08.2018, p. 841.

Research output: Contribution to journalArticle

Buccarelli, Mariachiara ; Marconi, Matteo ; Pacioni, Simone ; De Pascalis, Ivana ; D'Alessandris, Quintino Giorgio ; Martini, Maurizio ; Ascione, Barbara ; Malorni, Walter ; Larocca, Luigi Maria ; Pallini, Roberto ; Ricci-Vitiani, Lucia ; Matarrese, Paola. / Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. In: Cell death & disease. 2018 ; Vol. 9, No. 8. pp. 841.
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T1 - Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis

AU - Buccarelli, Mariachiara

AU - Marconi, Matteo

AU - Pacioni, Simone

AU - De Pascalis, Ivana

AU - D'Alessandris, Quintino Giorgio

AU - Martini, Maurizio

AU - Ascione, Barbara

AU - Malorni, Walter

AU - Larocca, Luigi Maria

AU - Pallini, Roberto

AU - Ricci-Vitiani, Lucia

AU - Matarrese, Paola

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N2 - The role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle progression, de facto exerting a cytostatic activity. Hence, it represents an important target for anticancer therapy. For example, temozolomide (TMZ), of use for glioblastoma (GBM) treatment, appears as capable of inducing autophagy partially inhibiting cancer cell proliferation. However, GBM, a very aggressive brain tumor with poor prognosis even after surgery and radio-chemotherapy, invariably recurs and leads to patient death. Since cancer stem cells have been hypothesized to play a role in refractory/relapsing cancers, in the present work we investigated if autophagy could represent a constitutive cytoprotection mechanism for glioblastoma stem-like cells (GSCs) and if the modulation of autophagic process could affect GBM growth and survival. Thus, in the present study we first evaluated the relevance of autophagy in GBM tumor specimens, then its occurrence in GSCs and, finally, if modulation of autophagy could influence GSC response to TMZ. Our results suggested that, in vitro, the impairing autophagic process with quinacrine, a compound able to cross the blood-brain barrier, increased GSC susceptibility to TMZ. Death of GSCs was apparently due to the iron dependent form of programmed cell death characterized by the accumulation of lipid peroxides called ferroptosis. These results underscore the relevance of the modulation of autophagy in the GSC survival and death and suggest that triggering of ferroptosis in GSCs could represent a novel and important target for the management of glioblastoma.

AB - The role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle progression, de facto exerting a cytostatic activity. Hence, it represents an important target for anticancer therapy. For example, temozolomide (TMZ), of use for glioblastoma (GBM) treatment, appears as capable of inducing autophagy partially inhibiting cancer cell proliferation. However, GBM, a very aggressive brain tumor with poor prognosis even after surgery and radio-chemotherapy, invariably recurs and leads to patient death. Since cancer stem cells have been hypothesized to play a role in refractory/relapsing cancers, in the present work we investigated if autophagy could represent a constitutive cytoprotection mechanism for glioblastoma stem-like cells (GSCs) and if the modulation of autophagic process could affect GBM growth and survival. Thus, in the present study we first evaluated the relevance of autophagy in GBM tumor specimens, then its occurrence in GSCs and, finally, if modulation of autophagy could influence GSC response to TMZ. Our results suggested that, in vitro, the impairing autophagic process with quinacrine, a compound able to cross the blood-brain barrier, increased GSC susceptibility to TMZ. Death of GSCs was apparently due to the iron dependent form of programmed cell death characterized by the accumulation of lipid peroxides called ferroptosis. These results underscore the relevance of the modulation of autophagy in the GSC survival and death and suggest that triggering of ferroptosis in GSCs could represent a novel and important target for the management of glioblastoma.

KW - Autophagy

KW - cancer

KW - Glioblastoma

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SN - 2041-4889

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