Crocin Ameliorated Atopic Dermatitis Induced in Mice by Inhibiting E-Cadherin/AKT Pathway

Abstract Background Circadian clock protein PERIOD2 (PER2) acts as a tumor suppressor in cancer; however, little is known about its involvement in chemosensitivity. Methods This study aimed to investigate the role and underlying mechanisms of PER2 in ovarian cancer sensitivity to cisplatin. Overexpression and knockdown of PER2 were performed to explore its role in ovarian cancer cell sensitivity to cisplatin both in vitro and in vivo. The protein levels of PI3K, AKT, caspase 3, E-cadherin, and other drug resistance-related molecules were determined in parental SKOV3 and SKOV3/DDP cells as well as in xenograft tumor tissues. Results Compared with parental cells, SKOV3/DDP cells had dramatically decreased PER2 expression, possibly due to hypermethylation in the PER2 promoter. PER2 overexpression significantly inhibited proliferation while promoting cisplatin-induced apoptosis in SKOV3 and SKOV3/DDP cells. In agreement, PER2-overexpressing SKOV3/DPP cells yielded significantly reduced tumor mass in cisplatin-treated mice compared with control cells. Mechanistically, PER2 overexpression remarkably reduced the protein amounts of PI3K, AKT, and MDR1, while increasing those of caspase 3 and E-cadherin in tumor tissues. Knockdown of PER2 exhibited opposite effects. PER2 overexpression also reduced the serum levels of TNF-α and IL-6 in tumor-bearing mice before the initiation of cisplatin treatment. Conclusion This study suggests that loss of PER2 contributes to cisplatin resistance in SKOV3 cells, possibly by activating the PI3K/AKT pathway and EMT, inhibiting apoptosis, and promoting drug efflux and inflammatory responses. Overexpression of PER2 could reverse these alterations and sensitize both parental SKOV3 and SKOV3/DDP cells to cisplatin.

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A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis

Journal of Experimental Medicine ◽

10.1084/jem.20130351 ◽

2013 ◽

Vol 210 (13) ◽

pp. 2939-2950 ◽

Cited By ~ 489

Author(s):

Maryam Salimi ◽

Jillian L. Barlow ◽

Sean P. Saunders ◽

Luzheng Xue ◽

Danuta Gutowska-Owsiak ◽

...

Keyword(s):

Atopic Dermatitis ◽

Mouse Skin ◽

Allergen Challenge ◽

Atopic Disease ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Type 2 Cytokines ◽

Skin Homing ◽

E Cadherin

Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1−/− and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.

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Distinct epithelial-to-mesenchymal transitions induced by PIK3CAH1047R and PIK3CB

Journal of Cell Science ◽

10.1242/jcs.248294 ◽

2021 ◽

Vol 134 (4) ◽

pp. jcs248294

Author(s):

Ersa Gjelaj ◽

Paul A. Hamel

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Low Frequency ◽

Akt Pathway ◽

Low Grade ◽

High Grade ◽

Wild Type ◽

Mesenchymal Transition ◽

Epithelial Sheets ◽

Phosphoinositide 3 Kinase ◽

E Cadherin

ABSTRACTThe most common PIK3CA mutation, producing the H1047R mutant of p110α, arises in myriad malignancies and is typically observed in low-grade breast tumours. In contrast, amplification is observed for wild-type PIK3CB, encoding p110β, and occurs at low frequency but in aggressive, high-grade metastatic tumours. We hypothesized that mutant p110αH1047R and wild-type p110β give rise to distinct transformed phenotypes. We show that p110αH1047R and wild-type p110β, but not wild-type p110α, transform MCF-10A cells and constitutively stimulate phosphoinositide 3-kinase (PI3K)-AKT pathway signalling. However, their resultant morphological transformed phenotypes are distinct. p110αH1047R induced an epithelial-to-mesenchymal transition (EMT) commensurate with SNAIL (also known as SNAI1) induction and loss of E-cadherin. Upon p110β expression, however, E-cadherin expression was maintained despite cells readily delaminating from epithelial sheets. Distinct from the prominent filopodia in p110αH1047R-expressing cells, p110β induced formation of lamellipodia, and these cells migrated with significantly greater velocity and decreased directionality. p110β-induced phenotypic alterations were accompanied by hyperactivation of RAC1; the dependency of transformation of p110β-binding to Rac1 revealed using a Rac1-binding mutant of p110β. Thus, PIK3CB amplification induces a transformed phenotype that is dependent upon a p110β-Rac1 signalling loop and is distinct from the transformed phenotype induced by p110αH1047R.

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PI 3K/ AKT pathway regulates E‐cadherin and Desmoglein 2 in aggressive prostate cancer

Cancer Medicine ◽

10.1002/cam4.463 ◽

2015 ◽

Vol 4 (8) ◽

pp. 1258-1271 ◽

Cited By ~ 18

Author(s):

Alison G. Barber ◽

Mireia Castillo‐Martin ◽

Dennis M. Bonal ◽

Angela J. Jia ◽

Benjamin A. Rybicki ◽

...

Keyword(s):

Prostate Cancer ◽

Akt Pathway ◽

Aggressive Prostate Cancer ◽

E Cadherin

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Estrogen stimulates the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway and regulation of its downstream targets E-cadherin and α-actinin-4

Molecular Medicine Reports ◽

10.3892/mmr.2014.2561 ◽

2014 ◽

Vol 10 (5) ◽

pp. 2433-2440 ◽

Cited By ~ 10

Author(s):

ZHIYING LU ◽

YING ZHANG ◽

XIAOHUI YAN ◽

YISONG CHEN ◽

XIANG TAO ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Akt Pathway ◽

Ovarian Cancer Cells ◽

Downstream Targets ◽

E Cadherin

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Akt/PKB enhances non-canonical Wnt signals by compartmentalizing β-Catenin

10.1101/149351 ◽

2017 ◽

Author(s):

Nicolas Aznar ◽

Nina Sun ◽

Ying Dunkel ◽

Jason Ear ◽

Matthew D. Buschman ◽

...

Keyword(s):

Cellular Proliferation ◽

Colony Growth ◽

Akt Pathway ◽

Cell Contact ◽

Long Distance ◽

Recycling Endosomes ◽

Dynein Motor ◽

Canonical Wnt ◽

The Impact ◽

E Cadherin

AbstractCellular proliferation is antagonistically regulated by canonical and non-canonical Wnt signals; their dysbalance triggers cancers. It is widely believed that the PI3-K→ Akt pathway enhances canonical Wnt signals by affecting transcriptional activity and stability of β-catenin. Here we demonstrate that the PI3-K→Akt pathway also enhances non-canonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide(PI)-binding domain of a multimodular signal transducer, Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell-cell contact sites, enhances non-canonical Wnt signals, and thereby, suppresses colony growth. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for crosstalk between Akt and the non-canonical Wnt pathway, but also reveals the impact of such crosstalk during cancer initiation and progression.

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