Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Abstract

Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. JNK | c-JunG astric cancer (GC) is a common cancer worldwide, associated with a high mortality despite its declining incidence in recent decades. Smoking, salted or smoked foods, and Helicobacter pylori appear to be major environmental inducers of GC (1-3). Although the role of H. pylori in causing mucosal effects has been investigated, which molecular signal(s) initiate the program of irreversible transformation remain unclear, and thus molecular targeting therapies for GC have not been well established.Mitogen-activated protein kinase (MAPK) pathways are important for the development of gastric tumorigenesis (4). Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPK kinase kinase (MAP3K), activated by various stress stimuli, including reactive oxygen species (ROS), TNF-α, and LPS (5-7). ASK1 activates the JNK and p38 signaling pathways and is required for both oxidative stress and cytokine-induced apoptosis (5). Furthermore, ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response (5,7,8) and has been reported to be involved in the pathogenesis of various human diseases, including neurodegenerative (9), cardiovascular (10), and inflammatory diseases (11,12). Additionally, ASK1 has been shown to participate in both colon (12) and skin (13) tumorigenesis through the regulation of inflammation and apoptosis. However, no reported study has demonstrated a role for ASK1 in gastric tumorigenesis.In this study, we examined the role of ASK1 in gastric tumorigenesis using both human GC samples and ASK1-deficient (ASK1 −/− ) mice. We demonstrated that ASK1 is important for gastric tumorigenesis through the regulation of cyclin D1 e...

Evidence for cell cycle suppression and microRNA regulation of cyclin D1 during anoxia exposure in turtles

“…27,30 Many studies have reported differential regulation of cyclin D1 and its effects on the proliferative state of diseased cells. [31][32][33] Mutations in the 3' UTR of cyclin D1 are also responsible for the hyperproliferative state associated with a variety of tumors types. 34 Cells expressing a cyclin D1 that lacks a 3' UTR also show a higher rate of proliferation.…”

Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an Activator of the GAPDH-Siah1 Stress-Signaling Cascade

“…In addition, ASK1 plays pivotal roles in a wide variety of cellular responses, which include, but are not limited to, apoptosis (30,31). Dysregulation of the ASK1 signaling pathway is closely linked to various diseases, such as cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases including polyglutamine-induced neurodegeneration and Parkinson disease (29,(32)(33)(34)(35)(36)(37).…”

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

“…The key initiator role of ASK1-3 in this pathway means that either too much or too little ASK activity can have pathological effects. For instance, inhibiting ASK1 is beneficial against gastric cancer (13,14), but inactivating mutations in ASK1 contribute to the development of melanoma (15, 16). In addition, ASK1 inhibitors have shown promise for treatment in mouse models of amyotrophic lateral sclerosis, highlighting it as a critical factor modulating cellular survival (17).…”