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

Abstract

BACKGROUND/AIMS:

p21-activated Ser/Thr kinase 1 (PAK1) is essential for the genesis and development of many cancers. The purpose of this study was to investigate the role of the PAK1-cyclic AMP response element-binding (CREB) axis in non-small cell lung cancer (NSCLC) tumorigenesis and its related mechanisms.

METHODS:

Western blot assay and immunohistochemical staining were employed to investigate the PAK1 and CREB expression in the tissue microarray of human squamous NSCLC. Co-immunoprecipitation and immunofluorescence confocal assays were performed to determine the link between PAK1 and CREB. NSCLC xenograft models were used to study oncogenic function of PAK1 in vivo.

RESULTS:

We observed that PAK1 and CREB expression levels were significantly elevated in human squamous NSCLC-tissue specimens, compared with those in adjacent normal bronchial or bronchiolar epithelial-tissue specimens, as well as their phosphorylated forms, based on western blotting. We showed in vitro that PAK1 knockdown by small-interfering RNA (siRNA) blocked CREB phosphorylation, whereas plasmid-based PAK1 overexpression resulted in CREB phosphorylation at Ser133, based on western blotting. In addition, PAK1 interacted with CREB in co-immunoprecipitation assays. Additionally, our in vitro findings detected by flow cytometry revealed that PAK1 silencing attenuated cell cycle progression, inducing apoptosis. Inhibition of PAK1 expression reduced tumor sizes and masses by modulating CREB expression and activation in xenograft models.

CONCLUSION:

These results suggest a novel mechanism whereby the PAK1-CREB axis drives carcinogenesis of squamous-cell carcinomas, and have important implications in the development of targeted therapeutics for squamous-cell lung cancer.

• Authors: Jae Heun Chung, Dae Hyun Kim, Yun Seong Kim, Bong Soo Son, Dohyung Kim, Chungsu Hwang, Donghoon Shin, Sang Gyun Noh, Jun Hee Han, Dae Kyung Kim, Jae Ho Kim, Ja Seok Koo, Hae Young Chung, Seong Hoon Yoon
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 50 Issue 1 Pg. 304-316 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30282071 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• CREB1 protein, human
• Cyclic AMP Response Element-Binding Protein
• RNA, Small Interfering
• PAK1 protein, human
• p21-Activated Kinases

Topics

• Aged
• Animals
• Apoptosis
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, mortality, pathology)
• Cell Line, Tumor
• Cyclic AMP Response Element-Binding Protein (genetics, metabolism)
• Female
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, metabolism, mortality, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Phosphorylation
• RNA Interference
• RNA, Small Interfering (metabolism, therapeutic use)
• Transcriptional Activation
• Up-Regulation
• p21-Activated Kinases (genetics, metabolism)