All-transretinoic acid induces autophagic degradation of ubiquitin-like modifier activating enzyme 3 in acute promyelocytic leukemia cells

Abstract

All-trans retinoic acid (ATRA) has demonstrated notable success in the treatment of acute promyelocytic leukemia (APL) by inducing granulocytic differentiation. The underlying mechanisms of ATRA therapeutic effects have not been entirely clarified. Here, we reported that the regulation of neddylation, a ubiquitination-like post-translational modification, was involved in the treatment of ATRA on APL. Treating APL cells with ATRA led to the degradation of UBA3, a subunit of neddylation E1. Lysosome-autophagy pathway but not proteasome pathway was responsible for the degradation of UBA3. Neddylation suppression in APL cells was capable of inducing apoptosis, differentiation and proliferation inhibition, suggesting a pivotal role of neddylation in APL cells. ATRA treatment also led to UBA3 degradation in primary APL cells. Taken together, our findings indicated that neddylation was important to maintain the malignant features of APL cells, and suppression of neddylation was involved in the effects of ATRA on APL cells.

Protein neddylation and its alterations in human cancers for targeted therapy

“…This line of study has not been pursued systematically. A recent report showed that NEDD8 E1 UBA3 can be degraded by lysosome-autophagy pathway but not proteasome pathway [171], suggesting a posttranslational regulation. Given that NEDD8 conjugation to a substrate is a dynamic process, yet another regulation could occur at the level of deneddylation system, involving COP9 signalosome, an enzyme with deneddylase activity [172–174], as well as NUB1 and NUB1L, two proteins known to mediate the proteasome-mediated degradation of NEDD8 and NEDD8 conjugates [175–177].…”

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

“…Nevertheless, this finding raises the possibility of overcoming the cell-autonomous TBK1 dependent blockade of autophagy as therapeutic strategy for ALS. In particular, we elected to screen small molecules targeting nuclear receptors because of their favorable pharmacokinetics (they often cross the blood-brain-barrier), their large impact on transcriptional responses [43][44][45][46] and the availability of large sets of nuclearreceptor targeting compounds amenable of drug repurposing. We found that a whole class of RARA agonists is able to accelerate the accumulation of SQSTM1 and increase the rate of MN apoptosis.…”

Effect of combination of all-trans retinoic acid and arsenic trioxide on apoptosis of acute promyelocytic leukemia cells

“…Prior to the use of targeted drugs in clinics, the mortality rate of APL was extremely high. However, with deepening of research on APL, many new treatment methods have emerged (16,17). Acute promyelocytic leukemia (APL) was a type of acute myeloid leukemia with the worst prognosis until ATRA and ATO were applied in clinical practice (16,17).…”

“…However, with deepening of research on APL, many new treatment methods have emerged (16,17). Acute promyelocytic leukemia (APL) was a type of acute myeloid leukemia with the worst prognosis until ATRA and ATO were applied in clinical practice (16,17). The combination therapy of ATRA and ATO has become the first-line treatment for patients who are intolerant of anthracycline (18).…”