Abstract
BackgroundIn cancer cells, autophagy can act as both tumor suppressor, when autophagic event eliminates cellular contends which exceeds the cellular capacity of regenerate promoting cell death, and as a pro-survival agent removing defective organelles and proteins and helping well-established tumors to maintain an accelerated metabolic state while still dealing with harsh conditions, such as inflammation. Many pathways can coordinate the autophagic process and one of them involves the transcription factors called PPARs, which also regulate cellular differentiation, proliferation and survival. The PPARγ activation and autophagy initiation seems to be interrelated in a variety of cell types.MethodsCaco-2 cells were submitted to treatment with autophagy and PPARγ modulators and the relationship between both pathways was determined by western blotting and confocal microscopy. The effects of such modulations on Caco-2 cells, such as lipid bodies biogenesis, cell death, proliferation, cell cycle, ROS production and cancer stem cells profiling were analyzed by flow cytometry.ResultsPPARγ and autophagy pathways seem to be overlap in Caco-2 cells, modulating each other in different ways and determining the lipid bodies biogenesis. In general, inhibition of autophagy by 3-MA leaded to reduced cell proliferation, cell cycle arrest and, ultimately, cell death by apoptosis. In agreement with these results, ROS production was increased in 3-MA treated cells. Autophagy also seems to play an important role in cancer stem cells profiling. Rapamycin and 3-MA induced epithelial and mesenchymal phenotypes, respectively.ConclusionsThis study helps to elucidate in which way the induction or inhibition of these pathways regulate each other and affect cellular properties, such as ROS production, lipid bodies biogenesis and cell survive. We also consolidate autophagy as a key factor for colorectal cancer cells survival in vitro, pointing out a potential side effect of autophagic inhibition as a therapeutic application for this disease and demonstrate a novel regulation of PPARγ expression by inhibition of PI3K III.
Highlights
In cancer cells, autophagy can act as both tumor suppressor, when autophagic event eliminates cellular contends which exceeds the cellular capacity of regenerate promoting cell death, and as a pro-survival agent removing defective organelles and proteins and helping well-established tumors to maintain an accelerated metabolic state while still dealing with harsh conditions, such as inflammation
We evaluated the involvement of autophagy and PPARγ with cell proliferation, cell death, lipid droplets formation, cell cycle, reactive oxygen species (ROS) production and cancer stem cells profile using colorectal cancer cells as a model
We investigated whether autophagic and PPARγmediated pathways could modify a phenotype aspect linked to cancer stem cells (CSCs) population, measured by CD24/CD44 differential expression
Summary
Autophagy can act as both tumor suppressor, when autophagic event eliminates cellular contends which exceeds the cellular capacity of regenerate promoting cell death, and as a pro-survival agent removing defective organelles and proteins and helping well-established tumors to maintain an accelerated metabolic state while still dealing with harsh conditions, such as inflammation. The genetic and epigenetic changes associated with the establishment of different gastrointestinal cancers were described in several recent studies [6, 7], lately, the key role of inflammation processes linked with the pathogenesis of colorectal cancer began to be described [8, 9]. The maintenance of the intestinal homeostasis depends on the balance between tolerance and inflammation conditions, which involves a variety of cellular pathways One of these pathways is autophagy, an intracellular process associated with the cell homeostasis regulation, innate immunity response and inflammation [12]. Pathogenesis such as Inflammatory Bowel Disease can be triggered by a slight deregulation on the autophagic process, which may result in tumor development [13]. Mutational events, which impair the autophagy pathways, have been shown to induce gastrointestinal problems, such as Crohn’s disease and increased risk of CRC development [14]
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