Differential cell fates induced by all-trans retinoic acid-treated HL-60 human leukemia cells

Abstract

HL-60 human leukemia cells, differentiated into a neutrophil lineage by all-trans retinoic acid (ATRA) treatment, express three members of the carcinoembryonic antigen (CEA) gene family, CEA-related cell adhesion molecule 1 (CEACAM1; CD66a), CEACAM3 (CD66d), and CEACAM6 (CD66c). CD66d is a neutrophil lineage-specific marker, and CD66a and CD66c are found on epithelial and other cells. HL-60 cells continuously treated with ATRA underwent apoptosis, and cells transiently treated for 1 day underwent cell-cycle arrest, entered into senescence, and exhibited reduced apoptosis with CD66-positive cells accounting for the majority of live cells. CD66 antigens were also induced in NB4 leukemic cells upon continuous treatment with ATRA. NB4 cells underwent apoptosis with a higher frequency in transient versus continuous-treated cells (38% vs. 19% at Day 5), in contrast to HL-60 cells that underwent cell-cycle arrest and senescence when transiently treated with ATRA. CD66 antigens were not induced in transient, ATRA-treated NB4 cells compared with HL-60 cells. Cell-cycle arrest in HL-60 cells involved reduction in expression levels of p21, cyclins D and E, while Rb1 exhibited reduction in protein levels without changes in mRNA levels over the time course of ATRA treatment. Analysis of several proapoptotic proteins implicated the activation of calpain and cleavage of Bax in the intrinsic apoptotic pathway, similar to published studies about the apoptosis of neutrophils. CD1d expression was also induced by ATRA in HL-60 cells and ligation with anti-CD1d antibody-induced apoptosis. In contrast, CD1d-positive primary monocytes were protected from spontaneous apoptosis by CD1d ligation. These studies demonstrate distinct cell fates for ATRA-treated HL-60 cells that provide new insights into ATRA-induced cell differentiation.

Regulation of multiple myeloma survival and progression by CD1d

“…48 Indeed, AIF was shown to mediate the caspase-independent cell death effect of Hu1D10 (apolizumab), an anti-HLA DR mAb currently tested in clinical trials. 49,50 Finally, while this work was under revision, it was reported by Ozeki and Shively that engagement of CD1d by anti-CD1d (clone 42.1) on the promyelocytic cell line HL60 induces considerable apoptosis, 51 thus independently corroborating our findings.…”

Antileukemic activity of combined epigenetic agents, DNMT inhibitors zebularine and RG108 with HDAC inhibitors, against promyelocytic leukemia HL-60 cells

“…In our study, we have observed that HL-60 cells treated using RA combinations with DNMT and HDAC inhibitors achieved accelerated differentiation into granulocytes, which subsequently die by apoptosis [52]. If HL-60 cell differentiation is mainly regulated through both retinoic acid receptors (RARs and RXRs), the apoptosis is modulated by activation of RXR, up-regulation of caspase activity [53,54], and the induction of the mitochondrial rather than the receptor-mediated apoptotic pathway [55]. Both processes are independently regulated in this cell line [56].…”

Re‐expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer

“…Continuous ATRA treatment of a human leukemia cell line induced the expression of CEACAM1 and resulted in apoptosis. 25 Gamma interferon also induced CEACAM1 in a colon cancer cell line. [26][27][28] However, as both ATRA and gamma interferon induce not only CEACAM1-S but also total CEACAM1, further investigation is required to develop an isoform-specific inducer.…”