Tanshinone IIA Attenuates Insulin Like Growth Factor 1 -Induced Cell Proliferation in PC12 Cells through the PI3K/Akt and MEK/ERK Pathways

Abstract

The insulin like growth factor 1 (IGF-1) and its receptor (IGF-1R) facilitate tumor proliferation and progression. Tanshinone IIA (TSN) is an active diterpene quinone isolated from the roots of the herbal plant Salvia miltiorrhiza. TSN inhibits the proliferation of various types of cancer cells but its role in the IGF-1R-induced proliferation of pheochromocytoma (PC12) cells and the potential mechanisms are largely unknown. This study aims to investigate the anti-proliferative effect of TSN in PC12 cells and its role on IGF-1R signaling transduction. PC12 cells were treated with IGF-1 with or without TSN, methyl thiazolytetrazolium (MTT) assay, and cell counting kit-8 and flow cytometry were used to evaluate the proliferation of PC12 cells. The role of TSN on the apoptosis of PC12 cells were detected by flow cytometry as well. The effects of TSN and IGF-1 on the phosphorylation of IGF-1R, protein kinase B (Akt), extracellular-signal related kinase 1/2 (ERK1/2) and other downstream targets were analyzed by Western blotting analysis. Our results showed that IGF-1 promoted the growth of PC12 cells in a dose-dependent manner and increased the phosphorylation of IGF-1R, whereas TSN attenuated the effect of IGF-1. Interestingly, TSN did not induce cell apoptosis in PC12 cells. Moreover, TSN attenuated the phosphorylation of Akt and ERK1/2 induced by IGF-1, and the phosphorylation of glycogen synthase kinase-3β, forkhead box O3a (FOXO3a) and c-Raf were also inhibited by TSN. Furthermore, TSN inhibited cell growth induced by IGF-1 and blocked the activation of IGF-1R in SH-SY5Y cells. Taken together, TSN has an inhibitory effect on the proliferation of PC12 cells via down-regulation of the phosphorylated IGF-1R and its downstream signaling.

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

“…In general, endoplasmic reticulum (ER) stress, apoptosis induction, and cell cycle arrest can inhibit cell proliferation. Previous studies reported that Tan IIA may inhibit the growth and proliferation of various cancer cells, such as lung, breast, liver, leukemia, and colon cancer Chen et al, 2012;Zhao et al, 2013;Lu et al, 2018;Wang et al, 2018;Zhou et al, 2018). The ER stress response is usually defined as the unfolded protein response, which is an imbalance between the accumulations of unfolded or misfolded proteins in the ER lumen .…”

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

“…The malignant melanoma cell lines, including SK-MEL-28, A875, B16, A375, and A2058 were obtained from the Chinese Center for Type Culture Collection (Wuhan, China) and cultured in DMEM (Dulbecco's modified Eagle's medium) with 10% FBS (fetal bovine serum) and streptomycin. The cytotoxicity assay was performed with the MTT method, as previously described [69][70][71].…”

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

“…Since ERKs are activated in response to extracellular stimuli, ERKs work as unique hubs that finely sense changes in the tumor microenvironment, producing adaptive responses of cancer cell [8,9,10]. RSKs and MSKs are downstream effectors of ERKs strongly involved in such stress adaptation.…”