Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells

Liu,Shi-Quan; Xu,Chun-Yan; Qin,Meng-Bin; Tan,Lin; Zhuge,Chun-Feng; Mao,Ye-Bo; Lai,Ming-Yu; Huang,Jie-An

doi:10.3892/or.2015.3923

Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells

Authors:
- Shi-Quan Liu
- Chun-Yan Xu
- Meng-Bin Qin
- Lin Tan
- Chun-Feng Zhuge
- Ye-Bo Mao
- Ming-Yu Lai
- Jie-An Huang
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Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: April 24, 2015 https://doi.org/10.3892/or.2015.3923
Pages: 2871-2882

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Abstract

Kinase suppressor of Ras 1 (KSR1) is a scaffold protein that modulates the activation of the oncogenic mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) signaling pathway. Ginkgo biloba extract (EGb) 761 has been demonstrated to possess antitumor activity that may be related to the KSR1‑mediated ERK signaling pathway. However, the roles and its underlying mechanism in gastric cancer are unclear. In the present study, 62 gastric cancer and matched normal tissues were exploited for immunohistochemistry and real‑time fluorescent quantitative PCR detection. Results of the immunohistochemistry showed that the expression of ERK1/2 and p-ERK1/2 was correlated to the expression of KSR1 and p-KSR1 in the gastric cancer tissues, and the overexpression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 was significantly associated with histological grade, TNM stage, lymph node and distant metastasis. Compared with the normal tissues, the relative mRNA copy values of KSR1, ERK1 and ERK2 in the cancer tissues were 2.43±0.49, 2.10±0.44 and 3.65±0.94. In addition, the expression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 in human gastric cancer multidrug resistant SGC-7901/CDDP cells was higher than that in the SGC-7901 cells as detected by the methods of immunocytochemistry and western blot analysis. EGb 761 not only suppressed expression of these proteins induced by cisplatin (CDDP) and etoposide in SGC-7901 cells, but also inhibited expression of these proteins in the SGC-7901/CDDP cells. Meanwhile, the proliferation‑suppressing and apoptosis‑inducing capacities of CDDP and etoposide were enhanced following combined treatment with EGb 761. Moreover, EGb 761 reduced the malondialdehyde (MDA) content and elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tumor cells. These results confirmed that activation of the KSR1-mediated ERK1/2 signaling pathway may contribute to tumorigenesis, metastasis and chemoresistance of human gastric cancer. EGb 761 enhanced the chemotherapy sensitivity and reversed the chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells, and the underlying mechanism may be related to its antioxidative activity.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, Asara JM, Cantley LC and Zheng B: Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell. 52:161–172. 2013. View Article : Google Scholar : PubMed/NCBI
3	Zhang H, Koo CY, Stebbing J and Giamas G: The dual function of KSR1: a pseudokinase and beyond. Biochem Soc Trans. 41:1078–1082. 2013. View Article : Google Scholar : PubMed/NCBI
4	Kortum RL, Fernandez MR, Costanzo-Garvey DL, Johnson HJ, Fisher KW, Volle DJ and Lewis RE: Caveolin-1 is required for kinase suppressor of Ras 1 (KSR1)-mediated extracellular signal-regulated kinase 1/2 activation, H-RasV12-induced senescence, and transformation. Mol Cell Biol. 34:3461–3472. 2014. View Article : Google Scholar : PubMed/NCBI
5	Llobet D, Eritja N, Domingo M, Bergada L, Mirantes C, Santacana M, Pallares J, Macià A, Yeramian A, Encinas M, et al: KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. Am J Pathol. 178:1529–1543. 2011. View Article : Google Scholar : PubMed/NCBI
6	Razidlo GL, Johnson HJ, Stoeger SM, Cowan KH, Bessho T and Lewis RE: KSR1 is required for cell cycle reinitiation following DNA damage. J Biol Chem. 284:6705–6715. 2009. View Article : Google Scholar : PubMed/NCBI
7	Lozano J, Xing R, Cai Z, Jensen HL, Trempus C, Mark W, Cannon R and Kolesnick R: Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res. 63:4232–4238. 2003.PubMed/NCBI
8	Cullis J, Meiri D, Sandi MJ, Radulovich N, Kent OA, Medrano M, Mokady D, Normand J, Larose J, Marcotte R, et al: The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cancer Cell. 25:181–195. 2014. View Article : Google Scholar : PubMed/NCBI
9	Stoeger SM and Cowan KH: Characterization of kinase suppressor of Ras-1 expression and anticancer drug sensitivity in human cancer cell lines. Cancer Chemother Pharmacol. 63:807–818. 2009. View Article : Google Scholar
10	Salerno M, Palmieri D, Bouadis A, Halverson D and Steeg PS: Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Mol Cell Biol. 25:1379–1388. 2005. View Article : Google Scholar : PubMed/NCBI
11	Liu SQ, Yu JP, Yu HG, Lv P and Chen HL: Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells. Dig Liver Dis. 38:310–318. 2006. View Article : Google Scholar : PubMed/NCBI
12	Ude C, Schubert-Zsilavecz M and Wurglics M: Ginkgo biloba extracts: A review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet. 52:727–749. 2013. View Article : Google Scholar : PubMed/NCBI
13	Tsai JR, Liu PL, Chen YH, Chou SH, Yang MC, Cheng YJ, Hwang JJ, Yin WH and Chong IW: Ginkgo biloba extract decreases non-small cell lung cancer cell migration by down-regulating metastasis-associated factor heat-shock protein 27. PLoS One. 9:e913312014. View Article : Google Scholar
14	Chen XH, Miao YX, Wang XJ, Yu Z, Geng MY, Han YT and Wang LX: Effects of Ginkgo biloba extract EGb761 on human colon adenocarcinoma cells. Cell Physiol Biochem. 27:227–232. 2011. View Article : Google Scholar : PubMed/NCBI
15	El Mesallamy HO, Metwally NS, Soliman MS, Ahmed KA and Abdel Moaty MM: The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats. Cancer Cell Int. 11:382011. View Article : Google Scholar : PubMed/NCBI
16	Park YJ, Kim MJ, Kim HR, Yi MS, Chung KH and Oh SM: Chemopreventive effects of Ginkgo biloba extract in estrogen-negative human breast cancer cells. Arch Pharm Res. 36:102–108. 2013. View Article : Google Scholar : PubMed/NCBI
17	Koltermann A, Liebl J, Fürst R, Ammer H, Vollmar AM and Zahler S: Ginkgo biloba extract EGb 761 exerts anti-angiogenic effects via activation of tyrosine phosphatases. J Cell Mol Med. 13:2122–2130. 2009. View Article : Google Scholar : PubMed/NCBI
18	Jiang XY, Qian LP, Zheng XJ, Xia YY, Jiang YB and Sun Y: Interventional effect of Ginkgo biloba extract on the progression of gastric precancerous lesions in rats. J Dig Dis. 10:293–299. 2009. View Article : Google Scholar : PubMed/NCBI
19	Xu AH, Chen HS, Sun BC, Xiang XR, Chu YF, Zhai F and Jia LC: Therapeutic mechanism of Ginkgo biloba exocarp polysaccharides on gastric cancer. World J Gastroenterol. 9:2424–2427. 2003.PubMed/NCBI
20	Mao YB, Liu SQ, Tan L, Zhou Q and Huang JA: EGb761 enhances cisplatin and etoposide-induced apoptosis of human gastric cancer SGC-7901 cells. Shijie Huaren Xiaohua Zazhi. 21:3330–3337. 2013.In Chinese.
21	Liu SQ, Yu JP, Chen HL, Luo HS, Chen SM and Yu HG: Therapeutic effects and molecular mechanisms of Ginkgo biloba extract on liver fibrosis in rats. Am J Chin Med. 34:99–114. 2006. View Article : Google Scholar : PubMed/NCBI
22	Kortum RL and Lewis RE: The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells. Mol Cell Biol. 24:4407–4416. 2004. View Article : Google Scholar : PubMed/NCBI
23	Gramling MW and Eischen CM: Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis. Cell Death Differ. 19:1220–1227. 2012. View Article : Google Scholar : PubMed/NCBI
24	Fukui H, Zhang X, Sun C, Hara K, Kikuchi S, Yamasaki T, Kondo T, Tomita T, Oshima T, Watari J, et al: IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling. Br J Cancer. 111:763–771. 2014. View Article : Google Scholar : PubMed/NCBI
25	Xing HR, Cordon-Cardo C, Deng X, Tong W, Campodonico L, Fuks Z and Kolesnick R: Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer. Nat Med. 9:1266–1268. 2003. View Article : Google Scholar : PubMed/NCBI
26	Smith JV and Luo Y: Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol. 64:465–472. 2004. View Article : Google Scholar : PubMed/NCBI
27	Mohanta TK, Tamboli Y and Zubaidha PK: Phytochemical and medicinal importance of Ginkgo biloba L. Nat Prod Res. 28:746–752. 2014. View Article : Google Scholar : PubMed/NCBI
28	Zhang Y, Chen AY, Li M, Chen C and Yao Q: Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. J Surg Res. 148:17–23. 2008. View Article : Google Scholar : PubMed/NCBI
29	Kang JW, Kim JH, Song K, Kim SH, Yoon JH and Kim KS: Kaempferol and quercetin, components of Ginkgo biloba extract (EGb 761), induce caspase-3-dependent apoptosis in oral cavity cancer cells. Phytother Res. 24(Suppl 1): S77–S82. 2010. View Article : Google Scholar
30	Akhiani AA, Werlenius O, Aurelius J, Movitz C, Martner A, Hellstrand K and Thorén FB: Role of the ERK pathway for oxidant-induced parthanatos in human lymphocytes. PLoS One. 9:e896462014. View Article : Google Scholar : PubMed/NCBI
31	Wang J, Lin D, Peng H, Huang Y, Huang J and Gu J: Cancer-derived immunoglobulin G promotes tumor cell growth and proliferation through inducing production of reactive oxygen species. Cell Death Dis. 4:e9452013. View Article : Google Scholar : PubMed/NCBI
32	Li W, Wu Z, Ma Q, Liu J, Xu Q, Han L, Duan W, Lv Y, Wang F, Reindl KM, et al: Hyperglycemia regulates TXNIP/TRX/ROS axis via p38 MAPK and ERK pathways in pancreatic cancer. Curr Cancer Drug Targets. 14:348–356. 2014. View Article : Google Scholar : PubMed/NCBI