Ninjurin 2 overexpression promotes human colorectal cancer cell growth in vitro and in vivo

Li, Gang; Zhou, Li-Na; Han, Yang; He, Xixi; Duan, Yuxia; Wu, Fang

doi:10.18632/aging.102336

Cited by 30 publications

(30 citation statements)

References 25 publications

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“…Moreover, both proteins have been associated with colon cancer. For instance, Ninj1 inhibits the development of colitis‐associated colon cancer by suppressing macrophage infiltration into tumors; while Ninj2 promotes human colorectal cancer cell growth 35,36 . However, its biological role in gut microbiota‐associated colitis has not yet been well characterized.…”

Section: Introductionmentioning

confidence: 99%

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

et al. 2020

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Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization and dysbiosis contributes to inflammatory bowel disease (IBD) pathogenesis. However, the molecular factors mediating colonic homeostasis are not well characterized. Here, we found that Ninjurin1 (Ninj1) limits colon inflammation by regulating macrophage polarization and microbiota composition under homeostatic conditions and during colitis development. Ninj1 deletion in mice induced hypersusceptibility to colitis, with increased prevalence of colitogenic Prevotellaceae strains and decreased immunoregulatory Lachnospiraceae strains. Upon co‐housing (CoH) with WT mice, Ninj1−/− mice showed increased Lachnospiraceae and decreased Prevotellaceae abundance, with subsequent improvement of colitis. Under homeostatic conditions, M1 macrophage frequency was higher in the Ninj1−/− mouse colons than wild‐type (WT) mouse colons, which may contribute to increased basal colonic inflammation and microbial imbalance. Following colitis induction, Ninj1 expression was increased in macrophages; meanwhile Ninj1−/− mice showed severe colitis development and impaired recovery, associated with decreased M2 macrophages and escalated microbial imbalance. In vitro, Ninj1 knockdown in mouse and human macrophages activated M1 polarization and restricted M2 polarization. Finally, the transfer of WT macrophages ameliorated severe colitis in Ninj1−/− mice. These findings suggest that Ninj1 mediates colonic homeostasis by modulating M1/M2 macrophage balance and preventing extensive dysbiosis, with implications for IBD prevention and therapy.

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Section: Introductionmentioning

confidence: 99%

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

et al. 2020

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“…2k), indicating apoptosis activation. However, in the primary colon epithelial cells ("pEpi1/2," from two donors 18 ), A1874 (100 nM) treatment failed to decrease cell viability ( Fig. 2l) and induce apoptosis activation (Fig.…”

Section: A1874 Induces Apoptosis Activation In Colon Cancer Cellsmentioning

confidence: 96%

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

Qin

Jin

et al. 2020

Cell Death Dis

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A1874 is a novel BRD4-degrading proteolysis targeting chimera (PROTAC). In primary colon cancer cells and established HCT116 cells, A1874 potently inhibited cell viability, proliferation, cell cycle progression, as well as cell migration and invasion. The BRD4-degrading PROTAC was able to induce caspase and apoptosis activation in colon cancer cells. Furthermore, A1874-induced degradation of BRD4 protein and downregulated BRD-dependent genes (c-Myc, Bcl-2, and cyclin D1) in colon cancer cells. Significantly, A1874-induced anti-colon cancer cell activity was more potent than the known BRD4 inhibitors (JQ1, CPI203, and I-BET151). In BRD4-knockout colon cancer cells A1874 remained cytotoxic, indicating the existence of BRD4-independent mechanisms. In addition to BRD4 degradation, A1874 cytotoxicity in colon cancer cells was also associated with p53 protein stabilization and reactive oxygen species production. Importantly, the antioxidant N-acetyl-cysteine and the p53 inhibitor pifithrin-α attenuated A1874-induced cell death and apoptosis in colon cancer cells. In vivo, A1874 oral administration potently inhibited colon cancer xenograft growth in severe combined immuno-deficient mice. BRD4 degradation and p53 protein elevation, as well as apoptosis induction and oxidative stress were detected in A1874-treated colon cancer tissues. Together, A1874 inhibits colon cancer cell growth through both BRD4-dependent and -independent mechanisms.

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“…The detailed protocols for apoptosis assays, including TUNEL staining, Annexin V-propidium iodide (PI) FACS, and caspase-3/-9 activity assays were described in detail in our previous studies 13,17,18 .…”

Section: Apoptosis Assaysmentioning

confidence: 99%

“…As described 13,16,17 , an equal amount protein lysates (30-40 μg per treatment in each lane) were separated by 10-12% SDSPAGE gels and thereafter transferred onto PVDF blots. Membranes were blocked and incubated with indicated primary antibodies, and subsequently incubated with corresponding secondary antibodies.…”

Section: Western Blottingmentioning

confidence: 99%

GDC-0349 inhibits non-small cell lung cancer cell growth

Han

Zhao

et al. 2020

Cell Death Dis

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Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related human mortality with a clear need for new therapeutic intervention. GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor. In A549 cells and primary human NSCLC cells, GDC-0349 inhibited cell growth, proliferation, cell cycle progression, migration and invasion, while inducing significant apoptosis activation. Although GDC-0349 blocked Akt-mTORC1/2 activation in NSCLC cells, it also exerted cytotoxicity in Akt1-knockout A549 cells. Furthermore, restoring Akt-mTOR activation by a constitutively-active Akt1 only partially attenuated GDC-0349-induced A549 cell apoptosis, indicating the existence of Akt-mTOR-independent mechanisms. In NSCLC cells GDC-0349 induced sphingosine kinase 1 (SphK1) inhibition, ceramide accumulation, JNK activation and oxidative injury. Conversely, N-acetylcysteine, the JNK inhibitor and sphingosine 1-phosphate alleviated GDC-0349-induced NSCLC cell apoptosis. In vivo, daily oral administration of GDC-0349 potently inhibited NSCLC xenograft growth in mice. Akt-mTOR in-activation, SphK1 inhibition, JNK activation and oxidative stress were detected in NSCLC xenograft tissues with GDC-0349 administration. In summary, GDC-0349 inhibits NSCLC cell growth via Akt-mTOR-dependent and Akt-mTOR-independent mechanisms.

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Ninjurin 2 overexpression promotes human colorectal cancer cell growth in vitro and in vivo

Cited by 30 publications

References 25 publications

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

GDC-0349 inhibits non-small cell lung cancer cell growth

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