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

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.

Scaffold Proteins in Gastrointestinal Tumors as a Shortcut to Oncoprotein Activation

“…A study observed that compared to the expression in the matched normal tissues, ERK1/2, p-ERK1/2, KSR1, and p-KSR1 were distinctly overexpressed in gastric cancer tissues, in association with TNM stage and the lymph metastasis [14] . Besides, the expressions of ERK1/2, p-ERK1/2, KSR1, and p-KSR1 are significantly related with each other, indicating that KSR1 might play a role in the oncogenesis and progression of gastric neoplasms [15] . Additionally, the KSR1-mediated ERK1/2 signaling pathway is inferred to be somehow associated with anticancer drug sensitivity and chemoresistance in GI tumors [13,15] .…”

“…Besides, the expressions of ERK1/2, p-ERK1/2, KSR1, and p-KSR1 are significantly related with each other, indicating that KSR1 might play a role in the oncogenesis and progression of gastric neoplasms [15] . Additionally, the KSR1-mediated ERK1/2 signaling pathway is inferred to be somehow associated with anticancer drug sensitivity and chemoresistance in GI tumors [13,15] .…”

“…Once activated, the complex relocates to the membrane, interacting with Raf and ERK1/2 and phosphorylating the cascade [11]. KSR1 has been found to be overexpressed in gastric cancers, and it is suggested that KSR1 is involved in oncogenesis and prognosis, anticancer drug sensitivity, and chemoresistance in GI tumors [13,15].…”

“…Meanwhile, the overexpression of KSR1 and p-KSR1 is somehow involved with TNM stage and lymph metastases in gastric cancer [14] . Besides, KSR1 offers resistance to multiple antitumor agents, such as cytochalasin H and tunicamycin, identified through drug screening assays [13] , while Ginkgo biloba extract (EGb) 761 has been shown to reduce KSR1-induced chemoresistance by virtue of its antioxidant effect [15] . As for FAK, a meta-analysis accomplished in 2016 [48] declared that upregulation of FAK resulted in worse overall survival (average hazard ratio = 2.073), and in particular, poorer overall survival was observed in gastric cancer (average hazard ratio = 2.073), whereas there seemed to be no correlation between FAK and neoplasm staging.…”

Effect of Enzyme Inhibitors on Terpene Trilactones Biosynthesis and Gene Expression Profiling in Ginkgo biloba Cultured Cells

“…The leaf extract of ginkgo has been employed for treating cerebrovascular and cardiovascular diseases for centuries [2]. Modern pharmacological studies showed that G. biloba extract could be also used for the treatment of chronic schizophrenia and Alzheimer's disease, as well as possessing antitumor activity [3][4][5]. Terpene trilactones, which include ginkgolides and bilobalide, are surmised to be responsible for most of the pharmacological properties of G. biloba extracts.…”