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Mol Cell Biochem. 2019 Jan;451(1-2):155-163. doi: 10.1007/s11010-018-3402-0. Epub 2018 Jul 17.

RACK1 deficiency synergizes with all-trans retinoic acid to induce apoptosis in human acute promyelocytic leukemia cells.

Author information

1
Henan University Joint National Laboratory for Antibody Drug Engineering, School of Medicine, Henan University, Kaifeng, 475004, People's Republic of China.
2
Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, People's Republic of China.
3
Henan University Joint National Laboratory for Antibody Drug Engineering, School of Medicine, Henan University, Kaifeng, 475004, People's Republic of China. LShL92627@163.com.
4
Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, People's Republic of China. JingW_biomed@163.com.
5
State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China. JingW_biomed@163.com.

Abstract

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome-autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL.

KEYWORDS:

APL; ATRA; Apoptosis; Autophagy; RACK1; Synergy

PMID:
30019299
DOI:
10.1007/s11010-018-3402-0
[Indexed for MEDLINE]

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