Chasing the FOXO3: Insights into Its New Mitochondrial Lair in Colorectal Cancer Landscape

Abstract

Colorectal cancer (CRC) poses a formidable challenge in terms of molecular heterogeneity, as it involves a variety of cancer-related pathways and molecular changes unique to an individual’s tumor. On the other hand, recent advances in DNA sequencing technologies provide an unprecedented capacity to comprehensively identify the genetic alterations resulting in tumorigenesis, raising the hope that new therapeutic approaches based on molecularly targeted drugs may prevent the occurrence of chemoresistance. Regulation of the transcription factor FOXO3a in response to extracellular cues plays a fundamental role in cellular homeostasis, being part of the molecular machinery that drives cells towards survival or death. Indeed, FOXO3a is controlled by a range of external stimuli, which not only influence its transcriptional activity, but also affect its subcellular localization. These regulation mechanisms are mediated by cancer-related signaling pathways that eventually drive changes in FOXO3a post-translational modifications (e.g., phosphorylation). Recent results showed that FOXO3a is imported into the mitochondria in tumor cells and tissues subjected to metabolic stress and cancer therapeutics, where it induces expression of the mitochondrial genome to support mitochondrial metabolism and cell survival. The current review discusses the potential clinical relevance of multidrug therapies that drive cancer cell fate by regulating critical pathways converging on FOXO3a.

Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements

“…APC mutations are present at the preliminary stages of neoplasia and are majorly linked with the classic tubular adenoma pathway and CIN cancers [ 33 , 34 , 35 , 36 ]. APC germline mutations give rise to familial adenomatous polyposis (FAP) syndrome (OMIM#: 608456), attenuated FAP, Gardner syndrome (OMIM#: 175100), Turcot syndrome (OMIM#: 276300), and other major hereditary predisposition events leading to CRC development [ 37 ].…”

FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

“…Upon metabolic stress (GR), AMPK directly modulates FOXO3a functions by phosphorylating six specific FOXO3a residues [38], and growing experimental evidence suggests that other sites may also be involved [140].…”

“…It has been shown that under GR conditions, AMPK promotes FOXO3a accumulation into the mitochondria of fibroblasts and skeletal myotubes, inducing the formation of a protein complex containing mtFOXO3a, SIRT3, TFAM, and mtRNA polymerase at mitochondrial DNA-regulatory regions, promoting the activation of mitochondrial gene expression and a subsequent increase in mitochondrial respiration [47,138]. Of note, AMPK can be triggered by mitochondrial ROS through an alternative pathway that involves the FOXO3a target genes MnSOD , CAT , and PGC-1α [122,140,162].…”

The Role of SIRT5 and p53 Proteins in the Sensitivity of Colon Cancer Cells to Chemotherapeutic Agent 5-Fluorouracil 

“…But besides that there are many studies that indicate the tumor suppressor roles of FOXO3a proteins [35,36]. Acetylation of FOXO has apoptosis promoting effect via activating the proapoptotic genes (Bim, p21, FASL6 etc) and as a result of deacetylation of FOXO3a by SIRT1 leads to cell survival and inhibition of FOXO3a mediated apoptosis [37,38]. According to our results, due to the reducing effect of 5-FU on SIRT5 expression, deacetylation of FOXO3a is alleviated and FOXO3a-dependent apoptotic pathways are induced.…”