biomolecules Review Regulation of Cancer Metastasis by TRAIL/Death Receptor Signaling You-Take Oh and Shi-Yong Sun * Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-404-778-2170 Abstract: Death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; TNFSF10) and their corresponding death receptors (e.g., DR5) not only initiate apoptosis through activation of the extrinsic apoptotic pathway but also exert non-apoptotic biological functions such as regulation of inflammation and cancer metastasis. The involvement of the TRAIL/death receptor signaling pathway in the regulation of cancer invasion and metastasis is complex as both positive and negative roles have been reported. The underlying molecular mechanisms are even more complicated. This review will focus on discussing current knowledge in our understanding of the involvement of TRAIL/death receptor-mediated signaling in the regulation of cancer cell invasion and metastasis. Keywords: TRAIL; death receptor; apoptosis; invasion; metastasis; cancer 1. Introduction Metastasis is a key cause of cancer death. To metastasize to distant organ sites, cancer cells must detach from the primary tumor sites (local invasion; intravasation), Citation: Oh, Y.-T.; Sun, S.-Y. translocate into the circulatory system, survive in the circulation and arrest at a distant Regulation of Cancer Metastasis by organ site (extravasation), and finally adapt to the new microenvironment of distant tissues TRAIL/Death Receptor Signaling. (micrometastasis formation; metastatic colonization) [1]. Therefore, cell death is a key Biomolecules 2021, 11, 499. https:// mechanism for preventing the dissemination of metastatic cells. Cell death can occur after doi.org/10.3390/biom11040499 the detachment of primary tumor cells from the extracellular matrix, in the circulation through tumor immune surveillance or destruction by mechanical stresses, and after Academic Editor: Ladislav Andˇera extravasation during the phase of micrometastasis formation in a secondary organ [2]. It has been estimated that only about <0.01% of cancer cells that enter the circulation are able Received: 4 February 2021 to eventually survive and develop lung metastasis [3,4]. This makes metastasis a highly Accepted: 24 March 2021 Published: 26 March 2021 inefficient process: very few of the cancer cells that migrate from the primary tumor can successfully colonize in distant sites [1]. Apoptosis represents a major form of cell death. Thus, the acquisition of apoptosis Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in resistance is a key hallmark of cancer and occurs early during tumorigenesis [5]. Ac- published maps and institutional affil- cordingly, it seems logical that the selection of cancer cells with greater deregulation of iations. apoptosis will be necessary for strong metastasis. It is well known that the extrinsic death receptor-mediated apoptotic pathway plays a critical role in host immune surveillance against cancer [6–8]. However, an increasing body of research suggests that this death signaling pathway also exerts non-apoptotic functions in enhancing cancer growth or metastasis. This review will primarily focus on discussing current knowledge in our under- Copyright: © 2021 by the authors. standing of the involvement of the extrinsic apoptotic pathway, particularly tumor necrosis Licensee MDPI, Basel, Switzerland. This article is an open access article factor-related apoptosis-inducing ligand (TRAIL)/death receptor-mediated signaling, in distributed under the terms and the regulation of cancer cell metastasis. conditions of the Creative Commons 2. TRAIL/Death Receptor-Mediated Apoptotic Signaling Pathway Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ There are two TRAIL death receptors in humans: death receptor 5 (DR5; also called 4.0/). TRAIL-R2, TNFRSF10B or Killer/DR5) and death receptor 4 (DR4; also called TRAIL-R1 Biomolecules 2021, 11, 499. https://doi.org/10.3390/biom11040499 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 16 Biomolecules 2021, 112., 499TRAIL/Death Receptor-Mediated Apoptotic Signaling Pathway 2 of 16 There are two TRAIL death receptors in humans: death receptor 5 (DR5; also called TRAIL-R2, TNFRSF10B or Killer/DR5) and death receptor 4 (DR4; also called TRAIL-R1 or TNFRSF10A).or TNFRSF10A).Both DR5 and BothDR4 DR5share and redu DR4ndant share functions redundant in triggering functions apoptosis in triggering apoptosis but have some butdistinct have biological some distinct functions, biological such as functions, regulation such of cancer as regulation cell metastasis, of cancer as cell metastasis, discussed below.as discussedIn contrast, below. there In is contrast, only one there TRAIL is only death one receptor TRAIL deathnamed receptor murine named murine TRAIL death receptorTRAIL death(mDR) receptor in mice (mDR)[9,10] or in mouse mice [9 homolog,10] or mouse of KILLER/DR5 homolog of (MK) KILLER/DR5 [11]. (MK) [11]. TRAIL ligationTRAIL to its functional ligation to cell its surface functional death cell receptors surface death or induction receptors of or death induction receptor of death receptor trimerization ortrimerization aggregation or(e.g., aggregation via overexpr (e.g.,ession via or overexpression agonistic antibodies) or agonistic leads antibodies)to re- leads to cruitment of therecruitment adaptor protein, of the adaptorFas-associ protein,ated death Fas-associated domain (FADD), death domain to the cytoplasmic (FADD), to the cytoplasmic region of the receptorregion of followed the receptor by recruitm followedent by of recruitment pro-caspase-8 of pro-caspase-8or pro-caspase-10. or pro-caspase-10. The The formation of thisformation death-inducing of this death-inducing signaling complex signaling (DISC) complex triggers (DISC) cleavage triggers and cleavage activa- and activation tion of caspase-8of or caspase-8 caspase-10, or caspase-10, which in turn which activates in turn downstream activates downstream caspase-3, caspase-3,-6, and -7, -6, and -7, and and eventual apoptosiseventual [12,13]. apoptosis Therefore, [12,13]. Therefore,TRAIL/death TRAIL/death receptor/FADD/caspase-8 receptor/FADD/caspase-8 signal- signaling ing normally triggersnormally apoptotic triggers cell apoptotic death (Figure cell death 1A). (Figure 1A). Figure 1. TumorFigure necrosis 1. Tumor factor-related necrosis factor-related apoptosis-inducing apoptosis-inducing ligand (TRAIL)/death ligand (TRAIL)/death receptor signalingreceptor signaling in the regulation of apoptosis andin the metastasis regulation of cancer of apoptosis cells. (A and) Under metastasis normal of apoptotic cancer cells. conditions (A) Under (e.g., normal in cancer apoptotic cells sensitive conditions to TRAIL with (e.g., in cancer cells sensitive to TRAIL with activated death receptor pathway), TRAIL ligation with activated death receptor pathway), TRAIL ligation with its death receptors (DR4 and DR5) or an agonistic antibody binding its death receptors (DR4 and DR5) or an agonistic antibody binding to a corresponding death recep- to a corresponding death receptor (DR4 or DR5) on the surface of cancer cells induces the formation of the death-inducing tor (DR4 or DR5) on the surface of cancer cells induces the formation of the death-inducing signaling signaling complexcomplex (DISC) (DISC) involving involving Fas-associated Fas-associated death death domain domain (FADD) (FADD) recruitment recruitment of pro-caspase-8 of pro-caspase-8 via its via death effector domain, resultingits death in effector caspase-8 domain, or -10 activationresulting in followed caspase-8 by or cleavage -10 activation and activation followed of by caspase-3, cleavage -6, and and activa- -7, and eventual execution oftion apoptosis of caspase-3, or anoikis. -6, and This -7, mechanismand eventual restricts execution the of formation apoptosis of or the anoikis. metastasis This and mechanism invasion restricts signaling complex (MISC) andthe subsequently formation of suppresses the metastasis cell invasion and invasion and metastasis. signaling Whencomple TRAIL/deathx (MISC) and receptors subsequently are inhibited sup- or their functions arepresses compromised, cell invasion available and FADDmetastasis. and caspase-8 When TRAIL/ may recruitdeath andreceptors stabilize are TNF-receptor-associatedinhibited or their functions factor (TRAF)2 with the helpare of compromised, S1P, resulting available in enhanced FADD TRAF2 and caspase-8 polyubiquitination may recruit and and activation, stabilize TNF-receptor-associated likely through a self-ubiquitination mechanism.factor This will(TRAF)2 further with lead the to help activation of S1P, of resulting ERK/JNK/AP-1 in enhanced signaling TRAF2 and polyubiquitination NF-κB activation, whichand activa- activates MMPs tion, likely through a self-ubiquitination mechanism. This will further lead to activation of (e.g., MMP1) and enhances the release of inflammatory cytokines (e.g., monocyte chemoattractant protein 1 (MCP1)) that ERK/JNK/AP-1 signaling and NF-κB activation, which activates MMPs (e.g., MMP1) and enhances promote invasion and metastasis of cancer cells. MCP1 may induce monocyte chemotactic protein-induced protein-1 the release of inflammatory cytokines (e.g., monocyte chemoattractant protein 1 (MCP1)) that pro- (MCPIP1) expression,mote invasion leading and metastasis