Role of Jagged1/STAT3 signalling in platinum‐resistant ovarian cancer

Abstract

Jagged1, the essential ligand of the Notch signalling pathway, is highly expressed in metastatic prostate cancer, and its high expression in breast cancer is linked to poor survival rates. However, the mechanism of Jagged1′s involvement in platinum‐resistant ovarian cancer has not been thoroughly elucidated to date. The purpose of the present study was to investigate the roles of Jagged1 in the platinum resistance of ovarian cancer and its possible mechanisms. Compared with a platinum responsive group of ovarian epithelial cell carcinomas, we found the positive staining intensity of Notch1, Notch2, Jagged1, STAT 3 and Epithelial‐mesenchymal transition ( EMT ) proteins were lower in a platinum‐resistant group. The DDP ‐resistant ovarian cancer cell line (C13K) had a higher IC 50 of DDP than its parental cell line ( OV 2008) ( P < 0.05) and acquired an EMT phenotype and invasive characteristics. Inhibiting or knockdown of Jagged1 expression could not only reduce its capacity of migration and invasion but also reverse EMT and down‐regulate the expression of serine 727‐phosphorylated STAT 3 ( pS 727) at the protein level but not total STAT 3 or tyrosine 705‐phosphorylated STAT 3 ( pY 705) in C13K cells. Furthermore, it was found that crosstalk between the Jagged1/Notch and JAK / STAT 3 signalling pathways were involved in Jagged1‐promoting EMT in C13K cells. Experiments in vivo showed a reduced micrometastatic tumour burden in the lung, liver and spleen of mice implanted with C13K cells with knocked‐down Jagged1 compared with mice implanted with control cells. All of these results demonstrate that Jagged1 can crosstalk with the JAK / STAT 3 pathway, and they all cooperate to promote the aberrant occurrence of EMT , further reinforcing the abilities of invasion and migration of platinum‐resistant ovarian cancer in vivo and in vitro.

Targeting cancer stem cell pathways for cancer therapy

“…DLL4 plays a vital role in regulating tumor angiogenesis. 594 Therefore, targeting DLL4 is another strategy to block Notch signaling, and this is being tested in the clinic. Demcizumab (OMP-21M18), a humanized IgG2 mAb that targets DLL4 and blocks its interactions with Notch receptors, was tested in a phase I dose escalation study with 55 patients with previously treated solid tumors.…”

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

“…IFN-c can induce epithelial-tomesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway [75], and STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC [76] PCa progression, cell proliferation, and inhibition of apoptosis [51,52] No direct analysis of these pathways in CTCs Wnt/ β-catenin Dysregulation of Wnt/β-catenin signaling has been implicated in the development of cancer in different tissues such as lung, skin, liver, and prostate [52], via regulating Zeb1 in CRC [77] Wnt/β-catenin pathway promotes the metastatic spread of prostate cancer cells by inducing EMT [78] Epithelial type CTCs and activation of Wnt/β-catenin signaling in lung cancer cells [79]. No report in PCa CTCs Notch Crosstalk between the Jagged1/Notch and JAK/STAT3 signaling pathways by promoting EMT through Jagged-1 in ovarian cancer [80] Notch signaling results in prostate tumor recurrence via EMT [81] Increased production of ROS results in the upregulation of Notch1 in CTCs in metastatic breast and melanoma cancer [82]. No report in PCa CTCs [89] N-cadherin [88] In the nucleus, AR acts as a transcription factor by binding to androgen-response elements (AREs) in the promoter region of androgen-regulated genes [95,96].…”

Gamma secretase inhibitors inhibit ovarian cancer development and enhance olaparib’s anti-ovarian cancer activity and its mechanism

“…β -catenin is the main downstream effector of the classic Wnt signaling pathway, mainly present in the cytoplasm. The cytoplasmic level is strictly controlled by the complex composed by adenomatous polyposis (APC), AXIN and glycogen synthase kinase 3β (GSK3β), and the complex induces its ubiquitination and proteasome-mediated degradation by phosphorylating serine on amino acid residue 37 (Ser37) or threonine on amino acid residue 41 (Thr41) of β-catenin [23][24] . Wnt signal transduction can induce β-catenin to enter the nucleus, regulate specific oncogenes, including c-MYC, cyclin D1 and survivin, and activate transcription factors together with the transcription enhancement factor / T cytokine (LEF / TCF) family to participate the occurrence and development of tumors [25][26] .…”