Abstract
Moringa oleifera Lam. is a tropical and subtropical plant that has been used for centuries as both food and traditional medicine. 4-[(α-L-Rhamnosyloxy) benzyl] isothiocyanate (MIC-1) is an active substance in M. oleifera, with anti-cancer activity. However, whether MIC-1 exerts anti-renal cancer effects is unknown. Therefore, the aim of the present study was to evaluate the effects of MIC-1 on the growth and migration of renal cell carcinoma (RCC) cells and to identify the putative underlying mechanism. We found that, among 30 types of cancer cells, MIC-1 exerted the strongest growth inhibitory effects against 786-O RCC cells. In addition, MIC-1 (10 μM) significantly inhibited the growth of five RCC cell lines, including 786-O, OSRC-2, 769-P, SK-NEP-1, and ACHN cells, but was not toxic to normal renal (HK2) cells. Also, MIC-1 suppressed 786-O and 769-P cell migration and invasion abilities, and reduced the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, MIC-1 induced apoptosis and cell cycle arrest, increased Bax/Bcl-2 ratio, and decreased cell cycle-related protein expression in 786-O cells and 769-P cells. Molecular docking and small-molecule interaction analyses with PTP1B both showed that MIC-1 inhibited PTP1B activity by binding to its active site through hydrogen bonding and hydrophobic interactions. Additionally, MIC-1 could suppress the growth and migration of 786-O cells by inhibiting PTP1B-mediated activation of the Src/Ras/Raf/ERK signaling pathway. In vivo experiments further showed that MIC-1 markedly inhibited the growth of xenograft tumors in mice, and greatly increased Bax/Bcl-2 ratio in tumor tissues. In addition, MIC-1 had no effect on the PTP1B-dependent Src/Ras/Raf/ERK signaling pathway in HCT-116 cells, Hep-G2 cells, and A431 cells. Overall, our data showed that MIC-1 could be a promising, non-toxic, natural dietary supplement for the prevention and treatment of renal cancer.
Highlights
Renal cell carcinoma (RCC) is a common and deadly disease with a worldwide estimate for 2020 of ∼431,000 new cases and ∼179,000 deaths (Global Cancer Observatory)
The results showed that MIC-1 significantly inhibited the growth of 26 of the 30 cancer cell lines (LoVo, PC-12, A375, 786-O, SKHep-1, SH-SY5Y, SK-MEL-1, Hep-G2, Hs578T, Caco-2, SK-BR3, SK-OV-3, HCT116, MDA-MB-468, SW480, MDA-MB-453, ZR-75-1, T-47D, HGC27, MGC80-3, MCF-7, PANC1, MDAMB-231, HT29, PC-3, and Caki-1), but had no effect on the growth of the other four cell lines (TF-1, HuH-6, A431, and SGC7901)
Compared with untreated 786-O cells overexpressing PTP1B, MIC-1 significantly decreased the cell proliferation rate, cell migration rate, the expression of p-Src (Tyr416) and p-ERK1/2, and increased the expression of p-Src (Tyr529) (Figures 5C–F). These results indicated that MIC-1 inhibited the growth and migration of renal cell carcinoma (RCC) cells through the PTP1B/Src/Ras/Raf/ERK signaling pathway
Summary
Renal cell carcinoma (RCC) is a common and deadly disease with a worldwide estimate for 2020 of ∼431,000 new cases and ∼179,000 deaths (Global Cancer Observatory). RCC accounts for 80–90% of all renal malignancies, and has an incidence rate of approximately 2.1% among systemic tumors (Siegel et al, 2018). Many targeted drugs are available for the treatment of RCC, a high recurrence rate and drug resistance remain the biggest challenges facing RCC patients (Ebos et al, 2009). Protein-tyrosine phosphatase 1B (PTP1B, known as PTPN1), a nonreceptor type phosphatase with oncogenic properties, is involved in growth factor signaling pathways (Bollu et al, 2017). PTP1B has been reported to exert its oncogenic activities through the activation of the nonreceptor tyrosine kinase Src (Zhang and Yu, 2012), which can enhance Ras/Raf/ERK/PI3K/mTOR pathway signaling and thereby promote tumor cell proliferation and metastasis (Penuel and Martin, 1999; Bollu et al, 2017). There is some evidence to suggest that Src may be associated with the malignancy of RCC cells and the poor prognosis of RCC patients, and the inhibition of Src may represent a promising option for the treatment of RCC (Yonezawa et al, 2005; Roseweir et al, 2016)
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