The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human  Osteoarthritis Chondrocytes

Liu, Zejun; Cai, Heguo; Zheng, Xiaomei; Zhang, Bing; Xia, Chun

doi:10.3390/ijms160817857

Cited by 20 publications

(18 citation statements)

References 27 publications

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“…Activated ERK could regulate autophagy either positively or negatively [24][25][26]. Meanwhile, PLCγ1 regulation of ERK phosphorylation has been demonstrated previously [27,28]. Our results that overexpression of PLCγ1 elevated ERK level concomitant with a decrease in LC3B-II and an increase in P62 exhibited the negative regulation of PLCγ1/ERK axis on autophagy in human lung adenocarcinoma A549 cells, thereby suggesting that the inhibition of PLCγ1/ERK axis contributed to autophagy induction in human lung adenocarcinoma A549 cells (Fig.8).…”

Section: Discussionsupporting

confidence: 74%

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Lü¹,

Fu²,

Chen³

et al. 2020

Int. J. Biol. Sci.

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Our previous studies indicated that phosphoinositide specific phospholipase Cγ1 (PLCγ1) was involved in autophagy induction in colon and hepatic carcinoma cells. However, whether and how PLCγ1 regulation in human lung adenocarcinoma is linked to autophagy remains unclear. Here, we assessed the protein expression of PLCγ1 in human lung adenocarcinoma tissue using immunohistochemistry assay and the relationship between PLCG1 and autophagy in The Cancer Genome Atlas Network (TCGA) using Spearman correlation analysis and GSEA software. Furthermore, the interaction between PLCγ1 and autophagy-related signal molecules was investigated in human lung adenocarcinoma A549 cells treated with different inhibitors or transduction with lentivirus-mediated PLCγ1 gene short-hairpin RNA (shRNA) vectors using MTT, clonogenicity, Transwell migration, RT-PCR, Caspase-3, mitochondrial transmembrane potential, and western blotting assays, as well as transmission electron microscope technique. Additionally, the effect of shRNA/PLCγ1 alone or combined with autophagic activator Lithium Chloride (LiCl) on tumor growth and metastasis was measured using immunohistochemistry and assays in A549 xenograft nude mouse model. The results showed that increased PLCγ1 expression occurred frequently in human lung adenocarcinoma tissue with higher grades of T in TNM staging classification. PLCγ1 significantly enriched in autophagic process and regulation, which negatively regulating autophagy was enriched in higher expression of PLCγ1. PLCγ1 inhibition partially reduced cell proliferation and migration of A549 cells, with an increased autophagic flux involving alterations of AMPKα, mTOR, and ERK levels. However, PLCγ1 inhibition-driven autophagy led to cell death without depending on Caspase-3 and RIP1. Additionally, the abrogation of PLCγ1 signaling by shRNA and combination with autophagic activator LiCl could efficaciously suppress tumor growth and metastasis in A549 xenograft nude mice, in combination with a decrease in P62 level. These findings collectively suggest that reduction of cell proliferation and migration by PLCγ1 inhibition could be partially attributed to PLCγ1 inhibition-driven autophagic cell death (ACD). It highlights the potential role of a combination between targeting PLCγ1 and autophagy pathway in anti-tumor therapy, which may be an efficacious new strategy to overcome the autophagy addition of tumor and acquired resistance to current therapy.

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Section: Discussionsupporting

confidence: 74%

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Lü¹,

Fu²,

Chen³

et al. 2020

Int. J. Biol. Sci.

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“…Moreover, inhibition of the p38-MARK signaling pathway suppressed apoptosis and expression of pro-inflammatory cytokines of IL-1,IL-6 and TNF-α in osteoarthritis chondrocytes [39]. Besides, the inhibition of ERK was involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis [40]. In our study, we explored that CXCR4 silencing blocked LPS-activated NF-κB and MAPK/ERK pathways in ATGC5 cells, further regulating cell viability, apoptosis and inflammatory injury in OA.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Long Non-Coding RNA RP11-445H22.4 Alleviates LPS-Induced Injuries by Regulation of MiR-301a in Osteoarthritis

Sun

Han

et al. 2018

Cell Physiol Biochem

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Background/Aims: Several long non-coding RNAs (lncRNAs) play vital roles in osteoarthritis (OA), whereas the role of lncRNA RP11-445H22.4 in OA remains unclear. The study aimed to investigate the effect of lncRNA RP11-445H22.4 on lipopolysaccharide (LPS)-induced cell viability, apoptosis and inflammatory injury of OA. Methods: The expression of RP11-445H22.4, miR-301a and CXCR4 in human cartilage ATDC5 cells were altered by transfection, and then cells were exposed to 5 µg/ml LPS for 12 h. Then cell viability, apoptosis, apoptosis-related factors and inflammatory cytokines were analyzed by CCK-8, flow cytometry, western blot, RT-qPCR and ELISA, respectively. Dual-luciferase reporter assay was performed to assess the binging sites of RP11-445H22.4 and miR-301a. The signal pathways of NF-κB and MAPK/ ERK were determined by western blot. Results: LPS reduced cell viability, increased apoptosis and stimulated release of IL-1β, IL-6, IL-8 and TNF-α. However, RP11-445H22.4 inhibition significantly rescued LPS-induced injuries by promoting cell viability, suppressing apoptosis and inflammatory cytokines secretions in ATDC5 cells. In addition, miR-301a directly bound to RP11-445H22.4, and suppression of miR-301a inversed the effects of RP11-445H22.4 inhibition. Furthermore, CXCR4 was a direct target of miR-301a, and CXCR4 silencing increased cell viability, decreased apoptosis and inflammatory cytokines secretions in LPS-treated ATDC5 cells. Besides, we found that CXCR4 silencing blocked LPS-activated NF-κB and MAPK/ERK pathways. Conclusions: The study indicated that lncRNA RP11-445H22.4-miR-301a-CXCR4 axis played an important role in cartilage ATDC5 cells and provided a theoretical basis of lncRNA RP11-445H22.4 in OA.

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“…However, the role of PLCγ1 in OA remains clear. Our recent observation also showed that PLCγ1 was expressed at elevated level in human OA chondrocytes than in normal chondrocytes, serving as a pivotal element of signal cascades constituted by ERK and mTOR to promote matrix degradation in human OA chondrocytes [ 13 , 14 ]. We then hypothesized that PLCγ1 could be involved in OA chondrocyte metabolism, contributing to matrix degradation.…”

Section: Introductionmentioning

confidence: 99%

The inhibition of PLCγ1 protects chondrocytes against osteoarthritis, implicating its binding to Akt

Cai

Chen

et al. 2017

Oncotarget

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Previous studies have addressed the involvement of phosphoinositide-specifc phospholipase γ1 (PLCγ1) and protein kinase B (PKB/Akt) in osteoarthritis (OA) pathogenesis, but it is not ascertained the possibility of them to be potential targets for OA therapy. Here, through local intra-articular injection of PLCγ or Akt inhibitor in a rat OA model induced by anterior cruciate ligament transaction plus medial meniscus resection, the architecture of chondrocyte and matrix organization of articular cartilage were observed using histopathological assays and Aggrecan, Col2, PLCγ1, and Akt levels were detected using immunohistochemistry assays. By treatment of Akt or PLCγ inhibitor and transfection of different PLCγ1- or Akt-expressing vectors in rat OA model chondrocytes, Aggrecan, Col2, PLCγ1, p-PLCγ1, Akt, and p-Akt levels were detected using western blotting analysis. The binding between PLCγ1 and Akt was assessed with co-immunoprecipitation assays in human OA chondrocytes. These results showed that PLCγ inhibition protected chondrocytes against OA, but Akt inhibition did not dramatically aggravate OA progression. There were mutual antagonism and binding between PLCγ1 and Akt that could be regulated by their phosphorylation levels. Consequently, the data reveal that the inhibition of PLCγ1 may provide an attractive therapeutic target for OA therapy, implicating its binding to Akt.

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The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Cited by 20 publications

References 27 publications

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Knockdown of Long Non-Coding RNA RP11-445H22.4 Alleviates LPS-Induced Injuries by Regulation of MiR-301a in Osteoarthritis

The inhibition of PLCγ1 protects chondrocytes against osteoarthritis, implicating its binding to Akt

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