Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells

Abstract

Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G(0)/G(1) apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up-regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF-7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IκBα in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.

Histometric analysis of vampire bat (Desmodus rotundus) testicles treated with coumestrol by oral route

“…Specifically, it has been demonstrated previously that exposure of adult male animals to a diet high in phytoestrogens (465 mg/g) disrupts spermatogenesis in a manner characterized by increased germ cell apoptosis (Assinder et al 2007;Seo et al 2011). Additionally, we consistently found larger spaces between the seminiferous tubules in the histological sections of COU-treated animals than in those of control animals.…”

Anticancer Activity of Pristimerin in Epidermal Growth Factor Receptor 2-Positive SKBR3 Human Breast Cancer Cells

“…This is the first report that pristimerin induces apoptosis via the extrinsic apoptotic pathway. One supportive study showed that apigenin induces apoptosis via the extrinsic pathway in HER2-positive breast cancer cells 58) ; however, we suggest that further investi gation is needed to identify the molecular mechanism of pris timerininduced apoptosis targeting HER2positive cancers.…”

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…Both proteins are not only persistently activated in cancer and essential for transducing cytoplasmic signals from extracellular stimuli, but they also function as nuclear transcription factors required for regulating genes involved in tumor proliferation, survival, angiogenesis and invasion, in addition to genes encoding key cancerpromoting inflammatory mediators (Karin and Greten, 2005;Baud and Karin, 2009;Yu and Jove, 2004;Yu et al, 2007;Darnell, 2002). NF-κB and STAT3 play a critical role in many cancers including, hepatic (He and Karin, 2011), prostate (Shanmugam et al, 2011), Lung (Tyagi et al, 2009) and breast cancer (Seo et al, 2012) which was evident from the previous reports.…”