Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling

Abstract

Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect of fenofibrate (FF) on their activity. A549 cells induced the disruption and local activation of endothelial continuum. These events were accompanied by epidermal growth factor (EGF) up-regulation in endothelial cells. Impaired A549 diapedesis and HUVEC activation were seen upon the chemical inhibition of connexin(Cx)43 functions, EGF/ERK1/2-dependent signaling, and RhoA/Rac1 activity. A total of 25 μM FF exerted corresponding effects on Cx43-mediated gap junctional coupling, EGF production, and ERK1/2 activation in HUVEC/A549 co-cultures. It also directly augmented endothelial barrier function via the interference with focal adhesion kinase (FAK)/RhoA/Rac1-regulated endothelial cell adhesion/contractility/motility and prompted the selective transmigration of epithelioid A549 cells. N-acetyl-L-cysteine abrogated FF effects on HUVEC activation, suggesting the involvement of PPARα-independent mechanism(s) in its action. Our data identify a novel Cx43/EGF/ERK1/2/FAK/RhoA/Rac1-dependent signaling axis, which determines the efficiency of lung cancer cell diapedesis. FF interferes with its activity and reduces the susceptibility of endothelial cells to A549 stimuli. These findings provide the rationale for the implementation of FF in the therapy of malignant lung cancers.

Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel

“…Furthermore, it can delay chemotherapy-induced microevolution, expansion and systemic dissipation of drug-resistant, invasive sub-clones of prostate cancer cells. Last but not least, FF has previously been shown to interfere with tumor angiogenesis and to augment endothelial barrier function [38,57,58]. Therefore, FF is a promising metronomic agent that can serve to enhance the efficiency of the palliative chemotherapy of prostate cancer.…”

“…Human prostate carcinoma DU145 (ATCC; HTB-81), PC3 cells (ECCAC; HTB-81) and their drug-resistant sub-lineages were routinely cultivated in DMEM/F12 HAM (Sigma, St. Louis, MO) medium supplemented with 10% fetal bovine serum (FBS) and antibiotics [19,38]. Human umbilical vein endothelial cells (HUVEC; Life Technologies Corporation, Carlsband, CA, USA) were cultured (up to six passages) in endothelial basal medium (EBM; Lonza, Basel, Switzerland) supplemented with 10% fetal bovine serum (FBS) and supplement cocktail (hydrocortisone, recombinant hEGF, bovine brain extract, gentamicin, amphotericin-B; all from Lonza [58]). For endpoint experiments, media supplemented with DCX and/or FF were added to cancer cell cultures at the concentrations given in the text.…”

“…These data were pooled and analyzed to calculate the averaged values of these parameters at the population level and to perform their statistical analysis (from no less than three independent experiments; number of cells >50 [60]). For transmigration assays, human umbilical vein endothelial cells (HUVEC) were seeded on coverslips at 2 × 10 4 cells/well and grown to confluence for 72 h. Thereafter, CellTracer Orange CMRA (10 μM, Life Technologies)-stained cancer cells were seeded (1300/cm 2 ) on HUVEC monolayers and incubated for 1 and 6 h [58]. Then, the specimens were stained against F-actin/DNA for microscopic estimation of the percentage of cancer cells capable of disrupting the endothelial continuum (transmigration).…”

Genome-wide RNA-sequencing dataset reveals the prognostic value and potential molecular mechanisms of lncRNA in non-homologous end joining pathway 1 in early stage Pancreatic Ductal Adenocarcinoma

“…Fenofibrate has anticancer effects in a variety of cancers 35 , and it increases the sensitivity of tumors to chemotherapy and radiotherapy 36 , 37 . A literature review revealed that fenofibrate has anticancer effects in many malignancies, including pancreatic cancer 38 , lung adenocarcinoma 39 , hepatocellular carcinoma 40 , melanoma 41 , glioblastoma 42 , 43 , oral cancer 44 , 45 , prostate cancer 46 , 47 , breast cancer 48 , neuroblastoma 49 , and angiosarcomas 50 . Fenofibrate also increases the sensitivity of esophageal carcinoma 51 , 52 and head and neck squamous cell carcinoma 37 to radiotherapy, and that of breast cancer to chemotherapy 36 .…”

CD44+ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations

“…24 They also account for its anticancer properties. 25,26 Interference of FF with cancer cell expansion and systemic dissipation 27 is accompanied by its effects on cancer "stroma," including vascular cells, 24,28 and cellular energy metabolism. 22,29,30 Thus, FF interferes with drug-resistance systems and sensitizes drug-resistant prostate cancer cells to chemotherapy.…”