AKT-induced PKM2 phosphorylation signals for IGF-1-stimulated cancer cell growth.

Young Soo Park,Eun Sil Yu,Young Il Yeom,Dong Chul Lee,Kyung Chan Park,Dong Joon Kim,Yeon-Mi You,Han Koo,Yuri Jung,Jung-Ae Kim,Se Hwan Jang,Jung Hee Cho,Zee-Yong Park,Suk-Jin Yang

doi:10.18632/oncotarget.10179

Abstract

Pyruvate kinase muscle type 2 (PKM2) exhibits post-translational modifications in response to various signals from the tumor microenvironment. Insulin-like growth factor 1 (IGF-1) is a crucial signal in the tumor microenvironment that promotes cell growth and survival in many human cancers. Herein, we report that AKT directly interacts with PKM2 and phosphorylates it at Ser-202, which is essential for the nuclear translocation of PKM2 protein under stimulation of IGF-1. In the nucleus, PKM2 binds to STAT5A and induces IGF-1-stimulated cyclin D1 expression, suggesting that PKM2 acts as an important factor inducing STAT5A activation under IGF-1 signaling. Concordantly, overexpression of STAT5A in cells deficient in PKM2 expression failed to restore IGF-induced growth, whereas reconstitution of PKM2 in PKM2 knockdown cells restored the IGF-induced growth capacity. Our findings suggest a novel role of PKM2 in promoting the growth of cancers with dysregulated IGF/phosphoinositide 3-kinase/AKT signaling.

Highlights

Insulin-like growth factors (IGFs) promote cell proliferation and inhibit apoptosis [1,2,3]
We examined the involvement of Pyruvate kinase muscle type 2 (PKM2) on the proliferation of NCI-H1299 lung cancer cells in response to Insulin-like growth factor 1 (IGF-1), given that high IGF-1 serum levels have been reported as a risk factor for lung cancer [7]
These results indicate that PKM2 may have important roles in cancer progression by promoting IGF-1induced cell proliferation

Summary

Introduction

Insulin-like growth factors (IGFs) promote cell proliferation and inhibit apoptosis [1,2,3]. IGFs are associated with the pathological development of many types of tumors, including breast cancer [4,5,6]. A high serum level of IGFs has been reported as a risk factor for pancreatic, lung, colorectal, and breast cancers [7,8,9]. IGF-1R contains a tyrosine kinase domain that is responsible for activating the phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/Raf/mitogen-activated protein kinase pathways that promote cell growth, transformation, migration, and survival [13,14,15]. Based on the reported associations between IGF signaling and the risk of cancer development, the IGF pathway has been suggested as a promising therapeutic target for many types of cancers. The regulatory mechanisms underlying the influence of IGF signaling on cancer development and progression remain to be fully elucidated

Methods

Results

Conclusion