Inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway

Abstract

Abstract. The activation of epidermal growth factor (EGF) through its receptor, EGFR, is one of the major mechanisms that mediate renal cell carcinoma (RCC) metastasis. Silibinin, a natural flavonoid antioxidant with pleiotropic anticancer capability, has shown anti-metastatic effects in a variety of cancers. However, the mechanism by which silibinin inhibits EGFR signal-induced migration and invasion of RCC cells is not clear. Here, we evaluated the potential roles of EGFR signaling cascade that affects RCC progression, and also investigated the inhibitory effect of silibinin on the EGFR signal-induced migration and invasion abilities of RCC cells. Our data indicated that silibinin inhibited migration and invasion of RCC cells in a dosedependent manner via blocking the EGFR signal, especially in the EGFR highly expressing RCC cells. Silibinin inhibited phosphorylation of EGFR and its downstream molecules ERK1/2 but did not affect phosphorylation of other downstream molecules, STAT3 and Akt, in human RCC cell lines. Moreover, our data suggested that silibinin significantly reduced the MMP-9 expression and its activity that was promoted by the EGFR signal, and also suppressed MMP9-dependent migration and invasion abilities of RCC cells. Taken together, this study clearly demonstrated that silibinin inhibited EGFR induced migration and invasion of RCC cells via blockade of EGFR/MMP-9 signaling. Thus, we suggest that silibinin could be used as a potential effective drug for the inhibition of RCC metastasis. IntroductionRenal cell carcinoma (RCC) accounted for 90-95% of neoplasms arising from the kidney and ~3.8% of adult malignancy in 2010 (1). Unfortunately, ~25-30% of patients have metastatic disease at first diagnosis, and >95% of these have multiple metastases (2). An aberrant activation of numerous signal pathways, including EGFR signal, has been recognized as a hallmark of cancer cell survival and progression (3). The studies also have revealed that overexpression of EGFR has been linked to RCC progression (4-6).Traditional systematic therapies for metastatic RCC tumors include immunotherapy, chemotherapy, and targeted therapy (7,8). However, low response rates have significantly retarded the efforts to improve the prognosis. There are still no effective methods for the treatment of metastatic RCC (9). Thus, searching for novel therapeutic methods or agents is needed for improving the efficacy against metastatic RCC.Acumulated evidence shows that silibinin, a natural flavonoid antioxidant, isolated from milk thistle (Silybum marianum), exerted pleiotropic anticancer capabilities in different human malignant tumors including prostate, bladder, breast, colon, and oral cancer (10-13). Due to the high efficacy of this drug against cancer as well as its non-toxic characteristics, the use of this drug provide a strong rationale for cancer prevention and adjuvant therapy compare with traditional chemical treatment.In our previous study, we found that silibinin inhibited cell proliferation in human RCC Caki-1 cells t...

Sex difference in EGFR pathways in mouse kidney-potential impact on the immune system

“…Liang et al reported the inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway [4]. The effect of EGR on renal cell carcinoma was also reported by others [5, 6].…”

Silibinin Inhibits Platelet-Derived Growth Factor-Driven Cell Proliferation via Downregulation of N-Glycosylation in Human Tenon's Fibroblasts in a Proteasome-Dependent Manner

“…Flavonoids, which bind to the ATP-binding site of several kinases, act as RTK inhibitors [39]. Silibinin is a flavonoid and impairs the EGF receptor regulated ERK signaling in various cancer cells [40]. Pre-incubation with silibinin was also reported to affect the early signaling events of the PDGFR activation including ERK and MEK phosphorylation [33].…”

Features of expression matrix metalloproteinases, their tissue inhibitors and renal cancer

“…Результаты исследования клинического значения уровня экспрессии ММП-9 клетками почечноклеточной карциномы в 249 образцах от пациентов и в клеточной линии почечно-клеточного рака человека Caki-2 продемонстрировали статистически значимую корреляцию (р<0,01) между выраженной экспрессией ММП-9 в клинических образцах и неблагоприятным прогнозом (низкой общей выживаемостью). Имеются сообщения об успешной попытке ингибирования транскрипции ММП-9 мРНК с последующим снижением инвазивной способности клеток Caki-2, что позволяет рассматривать ММП-9 как потенциальную мишень противоопухолевой терапии [27,30,32,35,44,53].…”