IL-33-induced JNK pathway activation confers gastric cancer chemotherapy resistance

Abstract

Abstract. Inflammation is regarded as one of the major hallmarks of tumors, and has a very close relationship with gastric cancer. Interleukin-33 (IL-33), a new member of the IL-1 family, plays an important role in both inflammatory disease and tumors. The present study was designed to explore the effects of IL-33 on the proliferation, drug sensitivity, and the invasiveness of gastric cancer cells in vitro. IL-33 at concentrations lower than 100 pg/ml did not alter the inhibitory rate of gastric cancer cells. Moreover, IL-33 at these low concentrations protected against platinum-induced apoptosis in various gastric cancer cell lines, yet not in normal gastric epithelial cells. We also found that IL-33 increased the activation of the JNK pathway, and enhanced the expression of ST2. Furthermore, SP600125, a selective inhibitor of the JNK pathway, significantly blocked the protective effects of IL-33 in gastric cancer cells. In addition, Matrigel invasion assay showed that IL-33 markedly promoted gastric cancer cell invasion. In conclusion, the present study demonstrated that IL-33 protected against platinum-induced apoptosis and promoted cell invasion via activation of the JNK pathway in gastric cancer cells. In light of the prevalence of platinumbased chemotherapeutics in the treatment of gastric cancer, our results suggest that the level of IL-33 should be monitored during the treatment of gastric cancer, particularly when using platinum-based chemotherapeutics. IntroductionGastric cancer is one of the most common types of cancers. Over 1.6 million individuals succumb to gastric cancer each year in China. The Chinese incidence of gastric cancer accounts for more than 40% of the worldwide occurrences. Moreover, the progression-free survival and overall survival rates of gastric cancer patients in China are much lower than those in Europe and the US. Therefore, research concerning the characteristics and pathogenesis of gastric cancer in Chinese patients is urgently needed.Gastric cancer can be influenced by a wide range of genetic and environmental factors. A clear association has been reported between gastric cancer and chronic inflammation (1-3). Pro-inflammatory factors, including interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF), may not only play roles in inflammation-associated carcinogenesis (4), but may also influence the chemotherapeutic sensitivity during gastric cancer treatment (5,6). IL-33 (previously known as NF-HEV), an 18-kDa protein, is a new member of the IL-1 family (7). Traditionally, the IL-1 family is well known for their effects on host defense, immune regulation and inflammation (7). However, recent research suggests that the IL-1 family is also involved in cancer development. For example IL-18, another member of the IL-1 family, acts as a pleiotropic cytokine in many types of cancer cells, and influences the invasion of gastric cancer cells under hypoxia (8). A high level of IL-18 in serum has been intensively associated with a wide variety of tumors, such as hepatocellular (9) a...

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“…In addition to cytoreductive surgery, cisplatin-based chemotherapy is one of the most important therapeutic strategies for ovarian cancer (2). Previous studies have shown that Wnt signaling pathway deregulation correlates with ovarian cancer cell proliferation, survival, invasion and metastasis (25,26,28,30,31). Furthermore, cisplatin chemoresistance has been an obstacle in the successful treatment of ovarian cancer (8,32,33).…”

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JNK signaling in cancer cell survival

“…Once JNK activity is inhibited, 5‐FU‐ and GEM increase intracellular ROS production and thereby promote the apoptosis of CSCs . JNK activation increases the expression of ST2 (an interleukin (IL)−33 reporter) in gastric cancer cells, making them resistant to platinum‐based chemotherapeutics . JNK1 inhibition sensitizes HT29 colon adenocarcinoma cells to oxaliplatin .…”

Cytokine networks and their association with Helicobacter pylori infection in gastric carcinoma

“…IL‐33 overexpressed in GC (Sun et al, ), stimulated the production of MMP‐3 and IL‐6 through activating ST2–ERK1/2 pathway, resulting in enhancement of cell invasion and migration (Yu et al, ). Ye et al () demonstrated that IL‐33 inhibited GC cell apoptosis induced by chemical compounds containing platinum via the ST2‐JNK axis and enhanced cell invasion through activating the JNK pathway. Therefore, the level of IL‐33 should be considered during the chemotherapy of GC.…”