MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells.
2022
Authors:
Mandić, MilošMisirkić Marjanović, Maja

Vučićević, Ljubica

Jovanović, Maja
Bošnjak, Mihajlo
Perović, Vladimir
Ristić, Biljana
Ćirić, Darko
Harhaji Trajković, Ljubica

Trajković, Vladimir
Document Type:
Article (Published version)

© 2022 Elsevier Inc.
Metadata
Show full item recordAbstract:
We investigated the mechanisms and the role of autophagy in the differentiation of HL-60 human acute myeloid leukemia cells induced by protein kinase C (PKC) activator phorbol myristate acetate (PMA). PMA-triggered differentiation of HL-60 cells into macrophage-like cells was confirmed by cell-cycle arrest accompanied by elevated expression of macrophage markers CD11b, CD13, CD14, CD45, EGR1, CSF1R, and IL-8. The induction of autophagy was demonstrated by the increase in intracellular acidification, accumulation/punctuation of autophagosome marker LC3-II, and the increase in autophagic flux. PMA also increased nuclear translocation of autophagy transcription factors TFEB, FOXO1, and FOXO3, as well as the expression of several autophagy-related (ATG) genes in HL-60 cells. PMA failed to activate autophagy inducer AMP-activated protein kinase (AMPK) and inhibit autophagy suppressor mechanistic target of rapamycin complex 1 (mTORC1). On the other hand, it readily stimulated the phosphorylation of mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) via a protein kinase C-dependent mechanism. Pharmacological or genetic inhibition of ERK or JNK suppressed PMA-triggered nuclear translocation of TFEB and FOXO1/3, ATG expression, dissociation of pro-autophagic beclin-1 from its inhibitor BCL2, autophagy induction, and differentiation of HL-60 cells into macrophage-like cells. Pharmacological or genetic inhibition of autophagy also blocked PMA-induced macrophage differentiation of HL-60 cells. Therefore, MAP kinases ERK and JNK control PMA-induced macrophage differentiation of HL-60 leukemia cells through AMPK/mTORC1-independent, TFEB/FOXO-mediated transcriptional and beclin-1-dependent post-translational activation of autophagy.
Keywords:
Autophagy; Beclin-1; Differentiation; ERK; JNK; LeukemiaSource:
Life Sciences, 2022, 297, 120481-Funding / projects:
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-200007)
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200110 (University of Belgrade, Faculty of Medicine) (RS-200110)
- COST Action CA15138
DOI: 10.1016/j.lfs.2022.120481
ISSN: 0024-3205
PubMed: 35304128
WoS: 000793214700005
Scopus: 2-s2.0-85126891813
URI
https://linkinghub.elsevier.com/retrieve/pii/S0024320522001813http://www.ncbi.nlm.nih.gov/pubmed/35304128
http://radar.ibiss.bg.ac.rs/handle/123456789/4947