FOXO1: Another avenue for treating digestive malignancy?

Abstract

Digestive malignancies are the leading cause of mortality among all neoplasms, contributing to estimated 3 million deaths in 2012 worldwide. The mortality rate hassurpassed lung cancer and prostate cancer in recent years. The transcription factor Forkhead Box O1 (FOXO1) is a key member of Forkhead Box family, regulating diverse cellular functions during tumor initiation, progression and metastasis. In this review, we focus on recent studies investigating the antineoplastic role of FOXO1 in digestive malignancy. This review aims to serve as a guide for further research and implicate FOXO1 as a potent therapeutic target in digestive malignancy.

Keywords: Akt; Digestive malignancy; Forkhead box O1; Hepatocellular carcinoma; microRNA.

Fig. 1. Structure of the transcription factor FOXO1

FOXO1 contains a forkhead DNA-binding domain (FHD), a nuclear export sequence (NES), a nuclear localization signal (NLS), and a transactivation domain (TAD). Sites of phosphorylation, ubiquitination, and acetylation are marked by different colors.

Fig. 2. FOXO1-involved signaling network

A variety of molecules regulate the expression and activity of FOXO1 and are involved in controlling survival of cancer cells.

Fig. 3. FOXO1 blocks neoplastic pathogenesis through multiple mechanisms in digestive malignancy

FOXO1 upregulates the levels of caspase and downregulates the levels of Bcl-2. Moreover, FOXO1 blocks cell cycle progression, meanwhile suppressing angiogenesis and enhancing apoptosis.