Activating Transcription Factor 5 Promotes Neuroblastoma Metastasis by Inducing Anoikis Resistance

Abstract

MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion–induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. Significance: This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP

“…As such, the peptides, associate with the leucine zippers of their obligate dimerization partners, but since lacking DNA binding domains, act as dominant-negative decoys to suppress their activities [1,7]. The peptides, designated as CP-dn-ATF5, Bpep and Dpep promote apoptotic death of a remarkably wide range of tumor cell types both in culture and in animal models [3,7,[10][11][12][13][14]. They also have a high degree of safety with no apparent effects on non-transformed cells in culture or in rodents [3,[10][11][12][13].…”

“…The peptides, designated as CP-dn-ATF5, Bpep and Dpep promote apoptotic death of a remarkably wide range of tumor cell types both in culture and in animal models [3,7,[10][11][12][13][14]. They also have a high degree of safety with no apparent effects on non-transformed cells in culture or in rodents [3,[10][11][12][13]. CP-dn-ATF5 binds and suppresses activity of CEBPB and CEBPD while Dpep and Bpep appear to associate with and inhibit ATF5 as well as CEBPB and CEBPD [1,7].…”

“…While the peptides promote apoptotic tumor cell death [11][12][13]15], the upstream mechanisms leading to such death are unclear. In addition, it is not fully understood how the peptides are capable Disclaimer/Publisher's Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s).…”

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP

“…As such, the peptides associate with the leucine zippers of their obligate dimerization partners, but since they lack DNA-binding domains, they act as dominant-negative decoys to suppress their activities [ 1 , 7 ]. The peptides, designated as CP-dn-ATF5 (cell-penetrating dominant-negative ATF5), Bpep and Dpep, promote apoptotic death of a remarkably wide range of tumor cell types both in culture and in animal models [ 3 , 7 , 10 , 11 , 12 , 13 , 14 ]. They also have a high degree of safety, with no apparent effects on non-transformed cells in culture or in rodents [ 3 , 10 , 11 , 12 , 13 ].…”

“…The peptides, designated as CP-dn-ATF5 (cell-penetrating dominant-negative ATF5), Bpep and Dpep, promote apoptotic death of a remarkably wide range of tumor cell types both in culture and in animal models [ 3 , 7 , 10 , 11 , 12 , 13 , 14 ]. They also have a high degree of safety, with no apparent effects on non-transformed cells in culture or in rodents [ 3 , 10 , 11 , 12 , 13 ]. CP-dn-ATF5 binds and suppresses activity of CEBPB and CEBPD, while Dpep and Bpep appear to associate with and inhibit ATF5 as well as CEBPB and CEBPD [ 1 , 7 ].…”