Dichotomy of all-trans retinoic acid inducing signals for adult T-cell leukemia

Abstract

We previously reported that all-trans retinoic acid (ATRA) inhibits growth in human T-cell leukemia virus type 1 (HTLV-1)-positive T-cell lines and fresh cells from patients with adult Tcell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed that NF-jB transcriptional activity as well as cell growth decreased significantly in HTLV-1-positive T-cell lines in the presence of ATRA. Furthermore, we observed that ATRA reduced HTLV-1 proviral DNA, HTLV-1 genes (gag, tax, or pol mRNA) using the real-time quantitative polymerase chain reaction. SIL-2R was reduced by ATRA in both protein level (culture supernantant) and mRNA level in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited RT activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. Moreover, AZT inhibited proviral DNA but not NF-jB transcriptional activity, and sIL-2R on HTLV-1; however, ATRA inhibited of NF-jB, proviral DNA and sIL-2R on HTLV-1. These results suggested that the decrease in sIL-2R induced by ATRA may be caused by the actions of a NF-jB inhibitor acting on the NF-jB/sIL-2R signal pathway. These results suggested that ATRA could have two roles, as a NF-jB inhibitor and as an RT inhibitor.

Retrovirus Infection and Retinoid

“…Furthermore, HTLV-1 proviral DNA load was also significantly decreased by ATRA in HTLV-1-positive T-cell lines (all five HTLV-1-positive T-cell lines at 48 hours, and ATL-2, HUT102, MT-4 and ED40515 at 72 hours). These results suggested that ATRA might act as a RT inhibitor (Yamaguchi et al, 2005). Moreover, HTLV-1 tax mRNA load was significantly suppressed by ATRA (HUT102 and MT-2 at 48hours).…”

“…HTLV-1 proviral DNA load was only decreased by VP-16 in MT-2. HTLV-1 proviral DNA load was significantly suppressed by AZT in the HTLV-1-positive T-cell lines (ATL-2 and MT-2 at 48 hours, and ATL-2, MT-2, MT-4 and ED40515 at 72 hours) (Yamaguchi et al, 2005). Furthermore, HTLV-1 proviral DNA load was also significantly decreased by ATRA in HTLV-1-positive T-cell lines (all five HTLV-1-positive T-cell lines at 48 hours, and ATL-2, HUT102, MT-4 and ED40515 at 72 hours).…”

“…Finally, we concluded that the mechanism of ATRA's action may be dichotomized into the inhibition of NF-κB's transcriptional activity related to HTLV-1 and inhibition of RT (Yamaguchi et al, 2005). It was reported that vitamin A supplementation reduced HIVassociated disease and slowed the progression toward AIDS (Fawzi et al, 2002).…”

“…In summary, we found that ATRA reduce HTLV-1 proviral DNA at mRNA level and RT activity of HTLV-1. These results suggest that the mechanism of ATRA's action may be dichotomized into inhibition of NF-κB transcriptional activity related to HTLV-1 and inhibition of RT (Yamaguchi et al, 2005). In another aspect on ATRA mechanism, we focused on the role of retinoids in inducing cellular senescence during the treatment of ATL (Maeda et al, 2011).…”

“…Moreover, HTLV-1 tax mRNA load was significantly suppressed by ATRA (HUT102 and MT-2 at 48hours). As ATRA reduced HTLV-1 proviral DNA load, we observed whether it degrades the RT that participates in the cycle of retroviral replication (Yamaguchi et al, 2005). HTLV-1-positive T-cell lines (1×10 5 /ml: total 20ml) were cultured with 10 -5 M ATRA, 64 μM AZT or control reagent.…”