Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma

Chung, Jong Il; Kim, Dae Hyun; Kim, Yun Seong; Son, Bong Soo; Kim, Dohyung; Hwang, Chungsu; Shin, Dong‐Hoon; Noh, Sang Gyun; Han, Jun; Kim, Dae Kyung; Kim, Jae Ho; Koo, Ja Seok; Chung, Hae Young; Yoon, Seong Hoon

doi:10.1159/000494007

Cited by 10 publications

(3 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AC2F cells were seeded at a density of 1 × 10 4 cells per well in a 12-well plate, following the method outlined in an earlier reference [ 80 ].…”

Section: Methodsmentioning

confidence: 99%

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

Kim,

Lee,

Noh

et al. 2024

Aging

View full text Add to dashboard Cite

FoxO6, an identified factor, induces hyperlipidemia and hepatic steatosis during aging by activating hepatic lipoprotein secretion and lipogenesis leading to increased ApoC3 concentrations in the bloodstream. However, the intricate mechanisms underlying hepatic steatosis induced by elevated FoxO6 under hyperglycemic conditions remain intricate and require further elucidation. In order to delineate the regulatory pathway involving ApoC3 controlled by FoxO6 and its resultant functional impacts, we employed a spectrum of models including liver cell cultures, aged rats subjected to HFD, transgenic mice overexpressing FoxO6 (FoxO6-Tg), and FoxO6 knockout mice (FoxO6-KO). Our findings indicate that FoxO6 triggered ApoC3-driven lipid accumulation in the livers of aged rats on an HFD and in FoxO6-Tg, consequently leading to hepatic steatosis and hyperglycemia. Conversely, the absence of FoxO6 attenuated the expression of genes involved in lipogenesis, resulting in diminished hepatic lipid accumulation and mitigated hyperlipidemia in murine models. Additionally, the upregulation of FoxO6 due to elevated glucose levels led to increased ApoC3 expression, consequently instigating cellular triglyceride mediated lipid accumulation. The transcriptional activation of FoxO6 induced by both the HFD and high glucose levels resulted in hepatic steatosis by upregulating ApoC3 and genes associated with gluconeogenesis in aged rats and liver cell cultures. Our conclusions indicate that the upregulation of ApoC3 by FoxO6 promotes the development of hyperlipidemia, hyperglycemia, and hepatic steatosis in vivo , and in vitro . Taken together, our findings underscore the significance of FoxO6 in driving hyperlipidemia and hepatic steatosis specifically under hyperglycemic states by enhancing the expression of ApoC3 in aged rats.

show abstract

“…AC2F cells were seeded at a density of 1 × 10 4 cells per well in a 12-well plate, following the method outlined in an earlier reference [ 80 ].…”

Section: Methodsmentioning

confidence: 99%

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

Kim,

Lee,

Noh

et al. 2024

Aging

View full text Add to dashboard Cite

show abstract

“…PAK1 inhibition was observed to induce cell cycle arrest via the accumulation of lung cancer cells in the G1 phase [13], and significantly impair tumor growth in lung cancer xenograft models, indicating that PAK1 drives NSCLC tumor proliferation [14,15]. However, further studies are warranted to determine whether PAK1 expression in NSCLC tumors correlates with the recurrence-free and overall survival of patients.…”

Section: Introductionmentioning

confidence: 99%

PAK1 as a Potential Therapeutic Target in Male Smokers with EGFR-Mutant Non-Small Cell Lung Cancer

et al. 2020

View full text Add to dashboard Cite

P21-activated kinases (PAKs) are serine/threonine protein kinases that contribute to several cellular processes. Here, we aimed to determine the prognostic value of PAK1 and its correlation with the clinicopathological characteristics and five-year survival rates in patients with non-small cell lung cancer (NSCLC). We evaluated PAK1 mRNA and protein expression in NSCLC cells and resected tumor specimens, as well as in healthy human bronchial epithelial cells and adjacent healthy lung tissues, respectively, for effective comparison. Immunohistochemical tissue microarray analysis of 201 NSCLC specimens showed the correlation of PAK1 expression with clinicopathological characteristics. The mRNA and protein expression of PAK1 were 2.9- and 4.3-fold higher in six of seven NSCLC cell types and human tumors (both, p < 0.001) than in healthy human bronchial epithelial BEAS-2B cells and adjacent healthy lung tissues, respectively. Decreased survival was significantly associated with PAK1 overexpression in the entire cohort (χ2 = 8.48, p = 0.0036), men (χ2 = 17.1, p < 0.0001), and current and former smokers (χ2 = 19.2, p < 0.0001). Notably, epidermal growth factor receptor (EGFR) mutation-positive lung cancer patients with high PAK1 expression showed higher mortality rates than those with low PAK1 expression (91.3% vs. 62.5%, p = 0.02). Therefore, PAK1 overexpression could serve as a molecular target for the treatment of EGFR mutation-positive lung cancer, especially among male patients and current/former smokers.

show abstract

“…34 In NSCLC, these kinases have been observed to induce cell cycle arrest, modulate epithelial-mesenchymal transformation, and significantly alter tumor growth in lung cancer xenograft models, indicating that these kinases could promote tumor proliferation and metastasis. 35 We also attempted to explore the key transcription regulators that mediate the differential expression of CXC chemokines and found that RELA, NFκB1, and SP1 might play a crucial role in the regulation of the gene expression of CXC chemokines. Persistent activation of RELA phosphorylation in lung tumorigenesis has been reported.…”

mentioning

confidence: 99%

Prognostic Significance and Therapeutic Target of CXC Chemokines in the Microenvironment of Lung Adenocarcinoma

Wang¹,

Li²,

Qi³

et al. 2022

IJGM

View full text Add to dashboard Cite

Background: Lung adenocarcinoma (LUAD) is one of the most important subtypes of lung cancer and has a high morbidity and mortality. Inflammatory CXC chemokines in tumor microenvironment can stimulate tumor growth, invasion, and metastasis, affecting the prognosis of patients. However, the differential expression profiles, prognostic values, and specific mechanisms of the CXC chemokine family in LUAD have not been clarified. Methods: Transcriptome expression profile data were extracted from TIMER and TCGA. GEPIA was used to compare the relationship between CXC chemokines and clinicopathologic parameters. The prognostic analysis was performed using a Kaplan-Meier curve in GEPIA. LinkedOmics and TRRUST were applied to conduct the enrichment analysis of the regulatory networks containing the kinase targets, miRNA targets, and transcriptional factor targets. The characteristics of immune infiltration and immune-related clinical outcomes were evaluated with TIMER algorithms. Single-cell RNA sequencing localization analysis of genes as prognostic biomarkers were performed by PanglaoDB. Results: Nine differentially expressed genes were identified in LUAD compared to normal tissues. Aberrant expression of CXCL2 (P =0.0017), CXCL13 (P= 0.0271), CXCL16 (P= 0.016), and CXCL17 (P= 2.14e-5) was significantly correlated with clinical cancer stage. Furthermore, patients with low gene transcription of CXCL 7 (P = 0.017) and high expression of CXCL 17 (P = 0.00045) had a better prognosis in LUAD. We also found that immune cell infiltration was significantly correlated with LUAD microenvironment mediated by CXC chemokines. Cox proportional hazard model test was conducted and indicated that B cell infiltration could prolong the survival of the LUAD patients. CXCL17 exerted anti-tumors effect through pulmonary alveolar type II cells according to singlecell analysis. Conclusion: Our research identified the aberrant expression profiles and prognostic biomarkers of CXC chemokines in LUAD. This detailed analysis of the regulatory factor networks for CXC chemokine gene expression may provide novel insights for selecting potential immunotherapeutic targets.

show abstract

Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma

Cited by 10 publications

References 22 publications

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

PAK1 as a Potential Therapeutic Target in Male Smokers with EGFR-Mutant Non-Small Cell Lung Cancer

Prognostic Significance and Therapeutic Target of CXC Chemokines in the Microenvironment of Lung Adenocarcinoma

Contact Info

Product

Resources

About