Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia

• Published in: Apoptosis (London) Vol. 13; no. 7; pp. 915 - 928
• Main Authors: Ozpolat, Bulent, Akar, Ugur, Zorrilla-Calancha, Isabel, Vivas-Mejia, Pablo, Acevedo-Alvarez, Marian, Lopez-Berestein, Gabriel
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01-07-2008; Springer US; Springer Nature B.V
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Arsenic; Arsenic Trioxide; Arsenicals - pharmacology; Base Sequence; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Eukaryotic Initiation Factor-2 - metabolism; Eukaryotic Initiation Factor-4G - antagonists & inhibitors; Eukaryotic Initiation Factor-4G - genetics; Eukaryotic Initiation Factor-4G - metabolism; Granulocytes - drug effects; Granulocytes - metabolism; Granulocytes - pathology; HL-60 Cells; Humans; Leukemia; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Models, Biological; Oncology; Original Paper; Oxides - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; TOR Serine-Threonine Kinases; Translocation; Tretinoin - pharmacology; Up-Regulation - drug effects; Virology; All; Acute promyelocytic leukemia; Leukemia; Arsenic trioxide; DAP5/p97; Differentiation; DAP5; Retinoic acid; Apoptosis
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-008-0222-9

All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells. Here we investigated the role and regulation of death-associated protein-5 (DAP5/p97/NAT1), a novel inhibitor of translational initiation, in APL cell differentiation and apoptosis. We found that ATRA markedly induced DAP5/p97 protein and gene expression and nuclear translocation during terminal differentiation of APL (NB4) and HL60 cells but not differentiation-resistant cells (NB4.R1 and HL60R), which express very low levels of DAP5/p97. At the differentiation inducing concentrations, ATO (<0.5 μM), dimethyl sulfoxide, 1,25-dihydroxy-vitamin-D3, and phorbol-12-myristate 13-acetate also significantly induced DAP5/p97 expression in NB4 cells. However, ATO administered at apoptotic doses (1-2 μM) induced expression of DAP5/p86, a proapoptotic derivative of DAP5/p97. ATRA and ATO-induced expression of DAP5/p97 was associated with inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Furthermore, DAP5/p97 expression was upregulated by inhibition of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway via LY294002 and via rapamycin. Finally, knockdown of DAP5/p97 expression by small interfering RNA inhibited ATRA-induced granulocytic differentiation and ATO-induced apoptosis. Together, our data reveal new roles for DAP5/p97 in ATRA-induced differentiation and ATO-induced apoptosis in APL and suggest a novel regulatory mechanism by which PI3K/Akt/mTOR pathway inhibition mediates ATRA- and ATO-induced expression of DAP5/p97.