Cell death and cytokine-mediated inflammatory responses to glucose deprivation in cancer cells

dc.contributor
Universitat de Barcelona. Facultat de Farmàcia
dc.contributor.author
Püschel, Franziska
dc.date.accessioned
2019-11-19T11:56:14Z
dc.date.available
2020-04-28T01:00:17Z
dc.date.issued
2019-10-31
dc.identifier.uri
http://hdl.handle.net/10803/667909
dc.description
Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Investigació Mèdica de Bellvitge (IDIBELL)
en_US
dc.description.abstract
Metabolic alterations in cancer cells are primarily caused by oncogenic mutations and cancer cells are more dependent on glucose compared to non-transformed tissue. Targeting the cancer metabolism opens up a new strategy for anti-cancer therapy. In order to make drugs more efficient and applicable in the clinic, it is necessary to fully investigate the cancer cell metabolism, especially of how cancer cells die upon glucose deprivation and more importantly, the consequences on the surrounding tissue when modifying or interfering with the metabolism. The unfolded protein response (UPR) is an intracellular stress response which is induced upon glucose deprivation. The activation of the three branches of the UPR facilitates pro-survival responses, however, chronic exposure to intra- or extracellular stress results in a switch towards a pro-death UPR response. The UPR is also described to be involved in pro-inflammatory responses due to the induction of cytokines and chemokines in several cell lines. Therefore, the release of cytokines upon glucose deprivation could facilitate the infiltration or exclusion of immune cells. We hypothesized that cancer cells die in an UPR dependent manner and that cancer cells release inflammatory cytokines upon glucose deprivation, which promote the infiltration of immune cells. We found that HeLa cells exposed to glucose deprivation, died in a TRAIL receptor 1 (DR4) and 2 (DR5) dependent manner, which was mediated by the activation transcription factor 4 (ATF4). Furthermore, we found the release of pro-tumorigenic cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6) and the leukemia inhibitory factor (LIF) from glucose deprived cancer cells as well as upon treatment with anti-metabolic drugs. We found that IL 6 and IL-8 but not LIF were regulated by ATF4 and p65 upon glucose deprivation. Moreover, the conditioned media of glucose deprived A549 promoted the migration of macrophage-like THP-1 cells as well as primary B cells and neutrophils isolated from human blood. These findings are important, since interfering with the cancer metabolism by using anti metabolic drugs could suppress the anti-tumorigenic effect of these drugs by promote pro-tumorigenic responses.
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dc.format.extent
219 p.
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application/pdf
dc.language.iso
eng
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dc.publisher
Universitat de Barcelona
dc.rights.license
L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.uri
http://creativecommons.org/licenses/by-nc/4.0/
*
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Càncer
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dc.subject
Cáncer
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dc.subject
Cancer
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dc.subject
Citoquines
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dc.subject
Citoquinas
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dc.subject
Cytokines
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dc.subject
Glucosa
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dc.subject
Glucose
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dc.subject.other
Ciències de la Salut
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dc.title
Cell death and cytokine-mediated inflammatory responses to glucose deprivation in cancer cells
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dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
615
en_US
dc.contributor.director
Muñoz Pinedo, Cristina
dc.contributor.tutor
Tauler Girona, Albert
dc.embargo.terms
6 mesos
en_US
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


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