TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells

Abstract

The inflammatory cytokine TGFβ is both a tumor suppressor during cancer initiation and a promoter of metastasis along cancer progression. Inflammation and cancer are strictly linked, and cancer onset often correlates with the insufficiency of vitamin D, known for its anti-inflammatory properties. In this study, we investigated the interplay between TGFβ and vitamin D in two models of human pancreatic cancer, and we analyzed the metabolic effects of a prolonged TGFβ treatment mimicking the inflammatory environment of pancreatic cancer in vivo. We confirmed the induction of the vitamin D receptor previously described in epithelial cells, but the inhibitory effects of vitamin D on epithelial–mesenchymal transition (EMT) were lost when the hormone was given after a long treatment with TGFβ. Moreover, we detected an ROS-mediated toxicity of the acute treatment with TGFβ, whereas a chronic exposure to low doses had a protumorigenic effect. In fact, it boosted the mitochondrial respiration and cancer cell migration without ROS production and cytotoxicity. Our observations shed some light on the multifaceted role of TGFβ in tumor progression, revealing that a sustained exposure to TGFβ at low doses results in an irreversibly increased EMT associated with a metabolic modulation which favors the formation of metastasis.

Vitamin D and Sulforaphane Decrease Inflammatory Oxidative Stress and Restore the Markers of Epithelial Integrity in an In Vitro Model of Age-Related Macular Degeneration

“…The results revealed that ARPE-19 cells did not express detectable basal levels of VDR since the signal corresponding to the receptor was not visible in the untreated cells (ctrl, C). However, the amount of protein was, unsurprisingly, greatly enhanced by the treatment with TGF-β since this induction has been previously described [ 52 ]. In contrast, VDR expression was not induced by SF treatment, neither at 1 µM nor 10 µM.…”

Whey Derivatives and Galactooligosaccharides Stimulate the Wound Healing and the Function of Human Keratinocytes through the NF-kB and FOXO-1 Signaling Pathways

“…Figure 3 shows that purified GOS, fermented product and butyrate induced the transcription of the respiratory complex and ATP synthase, whereas permeate was less effective. In this experimental set, the treatment with TGF-β was considered a positive control since the cytokine is a respiratory modulator [ 45 ]. Next, we wondered if any factor, and if so, which, could modulate the mitochondrial metabolism in response to GOS stimulation.…”

Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care—clinically relevant 3PM innovation

“…In addition, 1,25(OH) 2 D 3 reduces fibroblast differentiation and ECM formation via Smad2/3-dependent TGF-β1 signaling pathways [ 201 ] and the activation of VDR signals suppressed TGFβ-mediated EMT in a model of renal fibrosis [ 202 ]. Fiz et al [ 203 ] found that TGFβ/vitamin D interplay positively modulates mitochondrial activity in human pancreatic cancer cells. It was documented that activated VDR inhibits EMT through the modified epithelial mitochondrial function during the process of fibrosis [ 204 ].…”