PAK5-mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes breast cancer cell proliferation in vitro and in vivo

Zhang, Yingchun; Huo, Fu‐Chun; Wei, Lulu; Gong, Chan‐Chan; Pan, Yao‐Jie; Mou, Jie; Pei, Dong‐Sheng

doi:10.1186/s13046-017-0610-5

Cited by 42 publications

(31 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAK5‐directed GATA1 phosphorylation has been reported to induce epithelial–mesenchymal transition in breast cancer cells . In addition, PAK5 facilitates breast cancer cell proliferation by phosphorylating NF‐κB‐p65 . Although studies have suggested that PAK5 is a key regulator of breast cancer progression, the underlying molecular mechanism remains incompletely characterized.…”

Section: Introductionmentioning

confidence: 99%

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

Geng

Zhang

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Although clinically associated with the progression of multiple cancers, the biological function of p21‐activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5–aspartyl aminopeptidase (DNPEP)–ubiquitin‐specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5–DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin–proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5‐elicited signaling in breast cancer progression.

show abstract

Section: Introductionmentioning

confidence: 99%

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

Geng

Zhang

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…NF-κB p65 is a well-recognized anti-apoptotic transcription factor and abnormal expression or activation of NF-κB p65 has been found in multiple types of malignant cancers such as cervical cancer, esophageal squamous cancer, ovarian cancer, breast cancer and glioma et al [13,[26][27][28][29]. NF-κB promotes tumorigenesis and therapy resistance mainly through induction of master transcription factors including signal transducer and activator of transcription 3 (STAT3) and TAZ [30].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor I A Promotes Temozolomide Resistance in Glioblastoma via Transcriptional Regulation of Nuclear Factor κB Pathway

Wang

Zuo

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: Glioma is one of the most common primary brain tumors in human with severe mortality based on its therapy resistance and recurrence. Many molecular pathways and regulation factors have been proved to be required for GBM growth and therapy resistance, however, the underlying molecular mechanisms still remains unclear. Methods: Nuclear factor I-A (NFIA) was identified as a key candidate kinase encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, western blotting and in vivo xenograft models followed by temozolomide (TMZ) resistant U87 cell induction. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. At last, lentiviral silencing of NFIA was used to explore the potential downstream targets for NFIA in acquired TMZ resistance in GBM.. Results: We identified NFIA was the most correlated gene for TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated to adverse outcomes of glioma patients especially in GBM patients. Moreover, NFIA was functionally required for TMZ resistance of U87 cells while suppression of NFIA via lentivirus infection reduced cell proliferation, tumorigenesis as well as resistance to TMZ in GBM cells. Lastly, NFIA promoted acquired TMZ resistance in GBM via transcription activity thus regulated the expression of nuclear factor κB (NF-kB). Conclusions: Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to the acquired TMZ resistance in GBM, indicating that NFIA-NF-κB axis could be a new therapeutic target for TMZ resistant GBM.

show abstract

“…PAK7 was originally found in brain in which promotes the formation of filopodia in nerve cells 9 . However, recent studies have found that the expression level of PAK7 significantly increased in colorectal cancer 10 , 11 , ovarian cancer 12 , gastric cancer 13 - 15 , Neuroglioma 16 , 17 , Hepatocellular carcinoma 18 , 19 , Pancreatic cancer 20 , 21 , Osteosarcoma 22 , and breast cancer 23 - 25 , leading to increased proliferation and migration of tumor cells and inhibition of apoptosis. More importantly, PAK7 expression was positively correlated with the malignancy of colorectal cancer and ovarian cancer, suggesting that PAK7 indeed played an important role in tumor progression.…”

Section: Introductionmentioning

confidence: 99%

“…One study showed that PAK7 could phosphorylate GATA-binding factor 1 (GATA1) to recruit more Histone deacetylases 3/4 (HDA3/4) to E-cadherin promoter region, resulting in suppression of E-cadherin expression, which leads to epithelial-mesenchymal transition in breast cancer cells 23 . PAK7 can promote the phosphorylation and the nuclear translocation of p65 subunit of nuclear factor-kappaB (NF-κB), therefore promoting the proliferation and cell-cycle progression in breast cancer by increasing the expression of cyclin D1 in vitro and in vivo 25 . In addition, another study also reveals the PAK5-Egr1-MMP2 signaling pathway to be a critical regulator of cell migration and invasion in breast cancer cell 24 .…”

Section: Introductionmentioning

confidence: 99%

P21-activated kinase 7 (PAK7) interacts with and activates Wnt/β-catenin signaling pathway in breast cancer

Li¹,

Xu²,

He³

et al. 2018

J. Cancer

View full text Add to dashboard Cite

Background: Breast cancer is the highest incidence of tumor in women, which seriously threaten women's health. The occurrence and progression of breast cancer is linked to inactivation or downregulation of tumor suppressors, and activation or upregulation of oncogenes. However, the mechanism of PAK7 involving in the occurrence and progression of breast cancer is not yet fully understood.Methods: PAK7 expression was analyzed by RT-qPCR and immunohistochemistry and correlated with clinicopatholgical parameters in breast cancer tissue microarray. The effects of PAK7 on breast cancer cells were detected by CCK-8 assay, colon formation assay, wound healing and transwell assays, and flow cytometry. The relationship between PAK7 and Wnt/β-catenin signaling pathway was determined by western blotting, TOP/FOP flash, co-Immunoprecipitation and co-localization assays.Results: PAK7 expression was significantly increased in breast cancer tissues and positively correlated with pathological differentiation and TNM stage of breast cancer. Overexpression of PAK7 could significantly promote proliferation and migration of breast cancer cells, and inhibit apoptosis. In contrast, PAK7 knockdown significantly inhibited the proliferation and migration of breast cancer cells and promoted apoptosis. In addition, PAK7 could activate Wnt/β-catenin signaling pathway in breast cancer cells. Further study found that PAK7 could directly bind to GSK3β and β-catenin, and regulate β-catenin degradation by phosphorylating GSK3β.Conclusions: Our study demonstrated that PAK7, as an oncogene, involved in breast cancer progression by activating the Wnt/β-catenin signaling pathway, suggesting that the potential applicability of PAK7 as a target for breast cancer treatment.

show abstract

PAK5-mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes breast cancer cell proliferation in vitro and in vivo

Cited by 42 publications

References 33 publications

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

Nuclear Factor I A Promotes Temozolomide Resistance in Glioblastoma via Transcriptional Regulation of Nuclear Factor κB Pathway

P21-activated kinase 7 (PAK7) interacts with and activates Wnt/β-catenin signaling pathway in breast cancer

Contact Info

Product

Resources

About