MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells

Mandić, Miloš; Misirkic-Marjanovic, Maja; Vučićević, Ljubica; Jovanović, M.; Bošnjak, Mihajlo; Perović, Vladimir; Ristić, Biljana; Ćirić, Darko; Harhaji-Trajković, Ljubica; Trajkovič, Vladimir

doi:10.1016/j.lfs.2022.120481

Cited by 12 publications

(8 citation statements)

References 89 publications

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“…Moreover, our findings that PKC activity was correlated inversely with AMPK and positively with ERK phosphorylation, indicate that PKC could contribute to both AMPK inhibition and ERK activation in GBS leukocytes. This is consistent with the ability of PKC to inhibit AMPK [ 35 , 36 , 37 , 38 ] and activate ERK [ 39 , 40 , 41 , 42 ] in various experimental settings. Despite the increased activity, neither PKC nor ERK was associated with GBS disability or motor impairment scores, thus further emphasizing the potential value of AMPK signaling status as a marker of GBS severity and outcome.…”

Section: Discussionsupporting

confidence: 84%

Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome

Paunović

Perić

Vuković

et al. 2022

Cells

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AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.

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Section: Discussionsupporting

confidence: 84%

Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome

Paunović

Perić

Vuković

et al. 2022

Cells

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“…PMA-triggered cell differentiation induces cell-cycle arrest as well as elevated expression of macrophage markers CD11b, CD13, CD14, CD45, EGR1, CSF1R, and IL-8. 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 HL60 cells [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

EGCG Prevents the Transcriptional Reprogramming of an Inflammatory and Immune-Suppressive Molecular Signature in Macrophage-like Differentiated Human HL60 Promyelocytic Leukemia Cells

Kassouri

Torres

Suárez

et al. 2022

Cancers

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Background: The promyelocytic leukemia cell differentiation process enables recapitulation of the polarized M1 or M2 macrophage-like phenotype with inflammatory and immune-suppressive properties. While evidence supports the anti-inflammatory effect of dietary-derived epigallocatechin-3-gallate (EGCG), its impact on the onset of immune phenotype molecular signature remains unclear. Methods: Human HL60 promyelocytic cells grown in suspension were differentiated into CD11bHigh/CD14Low adherent macrophages with phorbol 12-myristate 13-acetate (PMA). Gelatin zymography was used to assess the levels of matrix metalloproteinase (MMP)-9, and total RNA was isolated for RNAseq and RT-qPCR assessment of differentially expressed gene levels involved in inflammation and immunity. Protein lysates were used to assess the phosphorylation status of signaling intermediates involved in macrophage-like cell differentiation. Results: Cell adhesion and induction of MMP-9 were indicative of HL60 cell differentiation into a macrophage-like phenotype. The extracellular signal-regulated kinase (ERK), glycogen synthase kinase (GSK)-3, p90 ribosomal S6 kinases (RSK), and cAMP-response-element-binding protein (CREB) were all phosphorylated, and EGCG reduced such phosphorylation status. Increases in inflammation and immunity genes included, among others, CCL22, CSF1, CSF2, IL1B, and TNF, which inductions were prevented by EGCG. This was corroborated by unbiased transcriptomic analysis which further highlighted the capacity of EGCG to downregulate the hematopoietic stem cell regulator CBFA2T3. Conclusion: EGCG inhibits inflammatory signaling crosstalk and prevents the onset of an immune phenotype in macrophage-like differentiated cells.

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“…37 Furthermore, FOXO1 has been reported to be involved in PMA-induced macrophage differentiation of leukaemia cells. 38 Long non-coding RNA ANCR could promote the invasion and migration of gastric cancer by inhibiting the expression of FOXO1 to inhibit macrophage M1 Polarization. 39 In this study, we found knockdown of RhoC increased the expression of PTEN and FOXO1.…”

Section: Discussionmentioning

confidence: 99%

Silencing of RhoC induces macrophage M1 polarization to inhibit migration and invasion in colon cancer via regulating the PTEN/FOXO1 pathway

Yang

Wang

Tian

2022

Int J Experimental Path

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Ras homologue family member C (RhoC) is an oncogene in diverse types of human cancers, whereas its regulatory mechanisms involving macrophage polarization is rarely investigated. This study is designed to explore the regulatory role of RhoC in colon cancer and the underlying molecular mechanisms involving macrophage polarization. We detected RhoC expression by quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blot, and analysed the biological function of RhoC knockdown in CC cells by the MTT, wound healing and transwell assay. Macrophage polarization‐associated markers, genes associated with migration, phosphatase and tensin homologue (PTEN) and forkhead box O (FOXO) were determined by qRT‐PCR and western blot. The xenograft tumour mouse model was used to assess the role of RhoC in vivo. RhoC is highly expressed in CC cells. The cell viability, invasion and migration abilities of CC cells were reduced by knockdown of RhoC. RhoC knockdown promoted M1 polarization, inhibited M2 polarization and decreased levels of genes associated with migration (matrix metalloproteinase‐2 and matrix metalloproteinase‐9). Silencing of RhoC inhibited tumour growth and expression of genes associated with migration in the xenografted model. In addition, silencing of RhoC promoted PTEN/FOXO1 expression, and PTEN inhibitor (SF1670) reversed the inhibitory effects of RhoC silencing. We demonstrated that silencing of RhoC reduced CC cells invasion and migration, and tumour growth by suppressing M2 macrophage polarization via regulating the PTEN/FOXO1 pathway.

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MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells

Cited by 12 publications

References 89 publications

Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome

Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome

EGCG Prevents the Transcriptional Reprogramming of an Inflammatory and Immune-Suppressive Molecular Signature in Macrophage-like Differentiated Human HL60 Promyelocytic Leukemia Cells

Silencing of RhoC induces macrophage M1 polarization to inhibit migration and invasion in colon cancer via regulating the PTEN/FOXO1 pathway

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