The role of pparγ and autophagy in ros production, lipid droplets biogenesis and its involvement with colorectal cancer cells modulation

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0451-5) contains supplementary material, which is available to authorized users.

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

“…We then analyzed the expression of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), which was confirmed to be highly expressed in starving and starved cells with respect to regularly fed cells. PPARγ, a lipid, glucose , and autophagy regulator , was highly expressed in either conditions at 55 days, decreasing at 75 days starvation, as well as at P6 and P13 (Fig. E, F) after starvation, with respect to regularly fed cells.…”

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

“…The role of lipophagy in cancer has not been addressed by many studies so far. While several reports have indicated tumour promoting effects of lipophagy [ 261 , 262 ], most studies so far suggest that lipophagy restricts tumourigenesis [ 263 , 264 , 265 , 266 ]. Microtubule-associated protein 1S (MAP1S)-mediated lipophagy promotes lipid droplet clearance and higher levels of MAP1S have been associated with reduced tumour growth and metastasis and an increased patient survival in clear-cell renal cell carcinoma [ 263 ].…”

Signaling and other functions of lipids in autophagy: a review

“…Because of its role in controlling the availability of nutrients, there has been an interest in targeting it as a treatment for cancer. In Colorectal cancer, studies with Caco-2, a common colorectal cancer cell line, have shown that activation of autophagy occurs following treatment with PPARγ agonist rosiglitazone [67]. In addition, inhibition of autophagy with 3-MA was observed to induce the expression of PPARγ.…”

“…In addition, inhibition of autophagy with 3-MA was observed to induce the expression of PPARγ. PPARγ was determined to cause the induction of PTEN, an antagonist to PI3K which dephosphorylates and reduces the concentration of PIP 3 [67]. This results in the overall inhibition of the mTOR pathway and induces autophagy.…”