Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

Abstract

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 colon cancer. However, the potential role and molecular events for KL in colon cancer remain unclear. The present study aimed to investigate the expression of KL in human colon cancer by immunohistochemistry, and to analyze the correlation between KL expression and clinicopathological characteristics of patients with colon cancer. Functional analysis after lentivirus-mediated gain of KL expression was used to assess the tumor growth and invasion in colon cancer cells in vitro and in vivo. The rate of KL expression was significantly decreased in cancer tissues compared with that in adjacent non-cancer tissues (ANCT) (60.3 vs.77.9%, P=0.022), and KL expression was negatively associated with Dukes staging (P=0.034) and depth of tumor invasion (P=0.008). Overexpression of KL in vitro inhibited cell proliferative activities and invasive potential in colon cancer cells, companied with decreased expression of p-IGF1R, p-PI3K, p-AKT, PCNA and MMP-2. In addition, the tumor volumes in the HT-29 subcutaneous tumor model treated with lentivirus‑mediated KL vector (Lv-KL) was significantly smaller than those of the negative control (NC) group (P<0.01). Taken together, our findings indicate that the expression of KL is downregulated in human colon caner and correlates with tumor invasion and Dukes staging, while overexpression of KL suppresses growth and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells, suggesting that KL may serve as a potential therapeutic target for the treatment of colon cancer.

Knockdown of type I insulin-like growth factor receptor inhibits human colorectal cancer cell growth and downstream PI3K/Akt, WNT/β-catenin signal pathways

“…It functions through enhancing the protein synthesis required for cell proliferation [17]. Nowadays, with more and more researches about IGF1R, many other regulatory factors has been presented, such as let-7d-5p, miR-493, miR-497 and tumor suppressor p53, klotho [18][19][20][21][22]. Inflammation is known as a hallmark of cancer wherein diverse immune cells exert either pro-or anti-tumor properties and affect therapeutic resistance [23].…”

miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

“…The involvement of this pathway in the development of colon cancer and metastasis, including cell proliferation, apoptosis and migration, has been extensively investigated (15)(16)(17)(18). Furthermore, the blockade of PI3K/Akt activity in colon cancer cells has shown promising anti-cancer effects (19)(20)(21)(22). Recent studies have demonstrated that the downstream factor of the PI3K/Akt pathway, the mammalian target of rapamycin (mTOR), is a potential therapeutic target in various types of cancer, including non-small cell lung cancer (23) (26), non-Hodgkin's lymphoma (27) and leukemia (28,29).…”

Klotho expression in cervical cancer: differential expression in adenocarcinoma and squamous cell carcinoma

“…Accumulating data indicate klotho as a potent tumour suppressor in a wide array of malignancies, including breast, lung and pancreatic cancers 13 15–18. Mechanisms mediating the tumour suppressor activities of klotho include modulation of bFGF signalling,13 18 inhibition of the insulin/IGF-1 pathways 13 15 18 19 and inhibition of the Wnt/β-catenin pathway 20 21…”