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

SIMPLE SUMMARY: TGFβ is a proinflammatory molecule produced by the tumor and active in its microenvironment. Its influence on cancer metabolism might explain its wide range of effects, but it is still poorly investigated. This study for the first time analyzes the TGFβ/vitamin D interplay in human pancreatic cancer cells and the effects of these two antagonistic molecules on the epithelial–mesenchymal transition, which is an early step of cancer progression. Data collected in this work also reveal the long-term metabolic effects of TGFβ, which are also relevant in the development of pancreatic cancer in vivo. The results of this research suggest that good levels of vitamin D can prevent the early stages of tumor transformation; on the contrary, chronic exposure to the inflammatory cytokine has irreversible consequences since it supports a prometastatic metabolism, confirming TGFβ as a crucial therapeutic target in pancreatic cancer. 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.