Klotho negatively regulated aerobic glycolysis in colorectal cancer via ERK/HIF1α axis

• Main Authors: Qingguo Li, Yaqi Li, Lei Liang, Jing Li, Dakui Luo, Qi Liu, Sanjun Cai, Xinxiang Li
• Format: Article
• Language: English
• Published: BMC 2018-06-01
• Series: Cell Communication and Signaling
• Subjects: Colorectal cancer; Klotho; Aerobic glycolysis
• Online Access: http://link.springer.com/article/10.1186/s12964-018-0241-2

Abstract Background Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers, including colorectal cancer. Recent years have witnessed the importance of metabolism transformation in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. Our previous studies demonstrated that KL played negative roles in colon cancer cell proliferation and metastasis. However, its role in the cancer cell reprogramming has seldom been reported. The aim of this study was to examine the role of KL in aerobic glycolysis in colorectal cancer. Methods Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and KL expression in colorectal cancer tissues. The impact of KL on glucose metabolism and its mechanisms were further validated in vitro and in vivo. Results Patients with lower KL expression exhibited higher 18F-FDG uptake (P < 0.05), indicating that KL might participate in aerobic glycolysis regulation. In vitro assay by using colon cancer cell lines further supported this observation. By overexpressing KL in HTC116 and SW480 cells, we observed that the glycolysis was inhibited and the mitochondrial respiration increased, indicating that KL was a negative regulator of aerobic glycolysis. To seek for the underlying mechanisms, we tried to dig out the relation between KL and HIF1α signaling pathway, and found that KL negatively regulated HIF1α protein level and transcriptional activity. Western blot analysis showed that KL overexpression negatively regulated ERK pathway, and KL regulated aerobic glycolysis in part through its regulation of ERK/ HIF1α axis. Conclusions Taken together, KL is a negative regulator of aerobic glycolysis and KL inhibited glucose metabolism transformation via the ERK/ HIF1α axis.