Eat this, not that! How selective autophagy helps cancer cells survive.
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ABSTRACT:
SUBMITTER: Mathew R
PROVIDER: S-EPMC4904891 | biostudies-other | 2015 Apr-Jun
REPOSITORIES: biostudies-other
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Project description:BackgroundAlcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood.MethodsWe utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells).ResultsUsing 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate.ConclusionsThis study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC.
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Project description:Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.
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Project description:Cytochrome c release from mitochondria promotes apoptosome formation and caspase activation. The question as to whether mitochondrial permeabilization kills cells via a caspase-independent pathway when caspase activation is prevented is still open. Here we report that proneural cells of embryonic origin, when induced to die but rescued by apoptosome inactivation are deprived of cytosolic cytochrome c through proteasomal degradation. We also show that, in this context, those cells keep generating ATP by glycolysis for a long period of time and that they keep their mitochondria in a depolarized state that can be reverted. Moreover, under these conditions, such apoptosome-deficient cells activate a Beclin 1-dependent autophagy pathway to sustain glycolytic-dependent ATP production. Our findings contribute to elucidating what the point-of-no-return in apoptosis is. They also help in clarifying the issue of survival of apoptosome-deficient proneural cells under stress conditions. Unraveling this issue could be highly relevant for pharmacological intervention and for therapies based on neural stem cell transfer in the treatment of neurological disorders.
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Project description:PurposeThe aim of this study was to explore head and neck cancer (HNC) patient experiences of a novel dietitian delivered health behaviour intervention.MethodsThis study is a qualitative study which employed semi-structured individual interviews using open and axial coding and then final selective coding to organise the data. Patients with HNC who had participated in a dietitian delivered health behaviour intervention to reduce malnutrition were invited to discuss their experience of this intervention. Individual interviews were conducted, transcribed and analysed using grounded theory.ResultsNine patients participated in the interviews. Four dimensions were identified in the initial coding process: 'information', which described patients' desire for tailored advice during their treatment; 'challenges of treatment experience', which described the difficulties related to treatment side effects; 'key messages: importance of eating and maintaining weight', which covered perceived integral messages delivered to patients by dietitians; and 'dietitian's approach' describing patient experiences of empathic and compassionate dietitians. Two overarching themes resulted from examining the connections and relationships between these dimensions: 'survival', a connection between eating and living; and 'support', describing the valued working partnership between dietitian and patient.ConclusionsDimensions and themes overlapped with the qualitative literature on HNC patient experience of treatment. However, some themes, such as the empowerment of a message linking eating to survival, appeared unique to this study. Patients found this message to be delivered in a supportive manner that motivated change.
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