The Polyphenols (−)-Epigallocatechin-3-Gallate and Luteolin Synergistically Inhibit TGF-β-Induced Myofibroblast Phenotypes through RhoA and ERK Inhibition

Abstract

The presence of reactive stroma, predominantly composed of myofibroblasts, is directly associated with and drives prostate cancer progression. We have previously shown that (−)-Epigallocatechin-3-gallate (EGCG), in the form of Polyphenon E, significantly decreases serum levels of HGF and VEGF in prostate cancer patients. Given that HGF and VEGF are secreted from surrounding tumor myofibroblasts, these observations suggested that EGCG may inhibit prostate cancer-associated myofibroblast differentiation. Herein, we demonstrate that micromolar combinations of EGCG and a second polyphenol, luteolin, synergistically inhibit TGF-β-induced myofibroblast phenotypes in prostate fibroblast cell lines, as observed primarily by potentiation of fibronectin expression. Functionally, EGCG and luteolin inhibited TGF-β-induced extracellular matrix contraction, an enhancer of tumor cell invasion. EGCG and luteolin inhibited downstream TGF-β-induced signaling, including activation of ERK and AKT, respectively, but mechanistically, only ERK appeared to be necessary for TGF-β-induced fibronectin expression. Furthermore, neither EGCG nor luteolin affected Smad signaling or nuclear translocation. Rho signaling was found to be necessary for TGF-β-induced fibronectin expression and EGCG and luteolin each reduced RhoA activation. Finally, EGCG and luteolin were shown to reverse TGF-β-induced fibronectin expression, implicating that these natural compounds may be useful not only in preventing but also in treating already activated myofibroblasts and the diseases they cause, including cancer. The ability of EGCG and luteolin to synergistically target myofibroblasts suggests that combined clinical use of these compounds could prevent or reverse cancer progression through targeting the tumor microenvironment, in addition to the tumor itself.

Comparative study of anti-angiogenic activities of luteolin, lectin and lupeol biomolecules

“…Luteolin and lupeol are small in size and have demonstrated to be better in inhibiting angiogenesis compared with lectin. Moreover, it has been shown by others that luteolin alone, and in combination with gefitinib or epigallocatechin-3-gallate [ 30 , 31 ] can inhibit another cancer but till date, nobody has shown the comparative effects of luteolin, with lupeol or lectin in colon cancer. Hence this manuscript is showing for the first-time comparative anti-angiogenic effect of luteolin with lupeol and lectin.…”

Gallic acid: a versatile antioxidant with promising therapeutic and industrial applications

“…7), the major constituents of green tea, are persistently emerging as remarkable antioxidant and anticancer agents both in vivo and in vitro. [124][125][126][127][128][129][130] Apart from being highly efficient in scavenging biologically damaging oxyl species (superoxide radical and singlet oxygen), these polyphenols have the unique ability to repair the Vitamin E radical. 95 These antioxidant properties of gallocatechins lay the foundation for the efficient chemoprevention of oxyl radical mediated degenerative diseases.…”

Intestine‐on‐chip device increases ECM remodeling inducing faster epithelial cell differentiation

“…In addition, lower levels of tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, IL-8, and transforming growth factor-β1 (TGF-β1) were detected in EGCG-treated compared with the control groups (untreated; Figure 5d). In particular, we analyzed the TGF-β1 release, that is a multifunctional signaling cytokine that has a potent fibrogenic action (Gray, Stephens, Bigelow, Coleman, & Cardelli, 2014). It is hypothesized that EGCG inhibits ECM gene expression by interrupting TGF-β signaling through attenuating oxidative stress (Yumei, Zhou, Zheng, & Chen, 2006).…”