C-FLIP, a Novel Biomarker for Cancer Prognosis, Immunosuppression, Alzheimer's Disease, Chronic Obstructive Pulmonary Disease (COPD), and a Rationale Therapeutic Target.

Ahmad R Safa,M Reza Saadatzadeh,Khadijeh Bijangi-Vishehsaraei,Krzysztof Kamocki

doi:10.36648/2472-1646.5.1.59

Abstract

Dysregulation of c-FLIP (cellular FADD-like IL-1β-converting enzyme inhibitory protein) has been shown in several diseases including cancer, Alzheimer’s disease, and chronic obstructive pulmonary disease (COPD). c-FLIP is a critical anti-cell death protein often overexpressed in tumors and hematological malignancies and its increased expression is often associated with a poor prognosis. c-FLIP frequently exists as long (c-FLIPL) and short (c-FLIPS) isoforms, regulates its anti-cell death functions through binding to FADD (FAS associated death domain protein), an adaptor protein known to activate caspases-8 and -10 and links c-FLIP to several cell death regulating complexes including the death-inducing signaling complex (DISC) formed by various death receptors. c-FLIP also plays a critical role in necroptosis and autophagy. Furthermore, c-FLIP is able to activate several pathways involved in cytoprotection, proliferation, and survival of cancer cells through various critical signaling proteins. Additionally, c-FLIP can inhibit cell death induced by several chemotherapeutics, anti-cancer small molecule inhibitors, and ionizing radiation. Moreover, c-FLIP plays major roles in aiding the survival of immunosuppressive tumor-promoting immune cells and functions in inflammation, Alzheimer’s disease (AD), and chronic obstructive pulmonary disease (COPD). Therefore, c-FLIP can serve as a versatile biomarker for cancer prognosis, a diagnostic marker for several diseases, and an effective therapeutic target. In this article, we review the functions of c-FLIP as an anti-apoptotic protein and negative prognostic factor in human cancers, and its roles in resistance to anticancer drugs, necroptosis and autophagy, immunosuppression, Alzheimer’s disease, and COPD.

Highlights

Introduction cFLIP or CLARP plays important roles in apoptosis, necroptotic cell death [1,2,3,4], and autophagy [1]
Disregulation of c-FLIP plays crucial roles in several diseases including cancer, Alzheimer's disease (AD), and chronic obstructive pulmonary disease (COPD). c-FLIP is a master apoptosis regulator frequently overexpressed in various malignancies and its upregulation is often correlated with a poor prognosis
It is well documented that c-FLIP isoforms induce resistance to death receptor ligands such as TRAIL, chemotherapeutic agents, and various cell death mechanisms in malignant cells, and is a rational target for modulating therapy-resistant human malignances Transitory pharmacological inhibition of c-FLIP is adequate to sensitize cancer cells to chemotherapeutics

Summary

Introduction

Introduction cFLIP or CLARP (caspase-like apoptosis-regulatory protein) plays important roles in apoptosis, necroptotic cell death [1,2,3,4], and autophagy [1]. C-FLIPL may be of importance in regulating the death receptor ligand-induced apoptosis, and in apoptotic processes triggered from within the cell [25]. Binding of TRAIL with its receptors DR4 and DR5 or interaction of Fas ligand (CD95L) to Fas receptor (CD95) triggers the death receptor (extrinsic) and subsequently mitochondrial apoptosis signaling (intrinsic) pathways through FADDdependent autocatalytic activation of caspases-8 and -10 and Bid cleavage to truncated Bid. c-FLIPL and c-FLIPS isoforms suppress caspase-8 and -10 activation, preventing the downstream apoptosis cascade (Modified from Safa [1]).

Results

Conclusion