Downregulation of caveolin-1 upregulates the expression of growth factors and regulators in co-culture of fibroblasts with cancer cells

Abstract

Reduced expression levels of caveolin-1 (Cav-1) in tumor stromal fibroblasts influences the occurrence and progression of tumors, particularly in breast cancer, but the relevant molecular mechanism is unclear. The present study aimed to clarify the potential mechanism underlying the promotion of tumor growth by reduced Cav-1 expression levels, by investigating Cav-1-targeted molecules in fibroblasts and breast cancer cells. The expression of growth factors in the ESF fibroblast cell line transfected with Cav-1 small interfering RNA (siRNA) was examined. The expression of apoptotic regulators in the BT474 breast cancer cell line that was co-cultured with the fibroblasts, was also investigated. The transfection of Cav-1-targeting siRNA in ESF cells resulted in efficient and specific inhibition of Cav-1 expression. The downregulation of Cav-1 increased the expression and secretion of stromal cell-derived factor-1 (SDF-1), epidermal growth factor (EGF) and fibroblast-specific protein-1 (FSP-1) in ESF cells. This resulted in the accelerated proliferation of the breast cancer cells. Tumor protein 53-induced glycolysis and apoptosis regulator (TIGAR) was upregulated in the BT474 cells under the condition of co-culture with Cav-1 siRNA fibroblasts, while levels of reactive oxygen species (ROS) were decreased, resulting in apoptosis inhibition in the breast cancer cells. These results demonstrated that the downregulation of Cav-1 promoted the growth of breast cancer cells through increasing SDF-1, EGF and FSP-1 in tumor stromal fibroblasts, and TIGAR levels in breast cancer cells. To the best of our knowledge, the present study supports the hypothesis that Cav-1 possesses tumor-suppressor properties, with the mechanism of Cav-1-dependent signaling involving the regulation of SDF-1, EGF, FSP-1 and TIGAR.

<p>Caveolin-1: a multifaceted driver of breast cancer progression and its application in clinical treatment</p>

“…In addition to a hypoxic TME, the effect of CAFs is another factor which influences the occurrence and progression of breast cancers. Reduced expression levels of Cav1 mRNA and Cav1 in CAFs trigger the expression and secretion of stromal cell-derived factor-1, EGF and fibroblast-specific protein-1 (FSP-1), and all of them can accelerate breast cancer cell proliferation rate 59…”

“…Cav1 can affect the apoptotic process by regulating the expression and activation of downstream proteins. Reduced expression levels of Cav1 in CAFs lead to upregulation of tumor protein 53-induced glycolysis and apoptosis regulator (TIGAR) in the BT474 cells, which functions to limit ROS, thus preventing cells from ROS-induced apoptosis 59. Docosahexaenoic acid (DHA) can facilitate caveolae internalization by sensitizing caveolae marker Cav1 to lysosomal marker LAMP-1, thereby decreasing caveolae-associated onco-protein levels via proteasomal and lysosomal pathways and decreasing HSP90 function 70…”

S100A4 in cancer progression and metastasis: A systematic review

“…Extracellular S100A4 stimulates the production of MMP13 in endothelial cells and promotes tumor angiogenesis [ 43 ] by the induced secretion of pro-inflammatory cytokines in tumor cells in the tumor microenvironment [ 67 ]. Caveolin-1 also promotes breast cancer progression by increasing the S100A4 expression in tumor stromal cells through manipulation of stromal cell-derived factor-1 (SDF-1), EGF and tumor protein p53-induced glycolysis, and apoptosis regulator (TIGAR) levels in breast cancer cells [ 68 ]. Similarly, the downregulation of serine/threonine kinase AKT3 increased migration and metastasis of triple negative breast cancer cells by the upregulation of S100A4 expression [ 69 ].…”

Quinalizarin exerts an anti-tumour effect on lung cancer A549 cells by modulating the Akt, MAPK, STAT3 and p53 signalling pathways

“…Reactive oxygen species (ROS) are one of the major causes of tumours and have significant roles in the processes of tumour progression, metastasis and apoptosis (19)(20)(21). Intracellular levels of ROS play key roles in survival and various physiological functions and also proven to be able to promote cell proliferation and apoptosis through threshold levels (22).…”