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Phosphorylation of the Cytoskeletal Protein CAP1 Regulates Non-Small Cell Lung Cancer Survival and Proliferation by GSK3?.

ABSTRACT: Adenylate cyclase-associated protein 1 (CAP1) is an evolutionarily conserved protein that regulates actin dynamics. Our previous study indicates that CAP1 is overexpressed in NSCLC tissues and correlated with poor clinical outcomes. Further establishing the role and dissecting underlying mechanisms are imperative before targeting CAP1 can become a possibility for cancer treatment. Here we report our findings that knockdown of CAP1 inhibited cell proliferation and induced apoptosis in vitro and in vivo. Moreover, phosphor mutants of CAP1 at the S307/S309 regulatory site had compromised rescue effects for both the invasiveness and the proliferation in CAP1-knockdown cells and GSK3? kinase inhibitor LiCl inhibited cell phosphorylation site S307/S309 by up-regulating the expression of p53, BAK, BAD and cleaved PARP induced ROS production, decreased lung cancer cell viability, adhesion, proliferation, migration and invasion, and induction of apoptosis. These novel mechanistic insights may ultimately open up avenues for strategies targeting CAP1 in the treatment of lung cancer, tailored for specific types of the highly diverse disease.

SUBMITTER: Xie S

PROVIDER: S-EPMC6096378 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Phosphorylation of the Cytoskeletal Protein CAP1 Regulates Non-Small Cell Lung Cancer Survival and Proliferation by GSK3β.

Xie Shuanshuan S Liu Yang Y Li Xuan X Tan Min M Wang Changhui C Field Jeffrey J Zhou Guo-Lei GL

Journal of Cancer 20180716 16

Adenylate cyclase-associated protein 1 (CAP1) is an evolutionarily conserved protein that regulates actin dynamics. Our previous study indicates that CAP1 is overexpressed in NSCLC tissues and correlated with poor clinical outcomes. Further establishing the role and dissecting underlying mechanisms are imperative before targeting CAP1 can become a possibility for cancer treatment. Here we report our findings that knockdown of CAP1 inhibited cell proliferation and induced apoptosis <i>in vitro</i ...[more]

PMID: 30123351

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Project description:PurposeCyclase-associated protein 1 (CAP1) is a ubiquitous protein which regulates actin dynamics. Previous studies have shown that S308 and S310 are the two major phosphorylated sites in human CAP1. In the present study, we aimed to investigate the role of CAP1 phosphorylation in lung cancer.MethodsMassive bioinformatics analysis was applied to determine CAP1's role in different cancers and especially in lung cancer. Lung cancer patients' serum and tissue were collected and analyzed in consideration of clinical background. CAP1 shRNA-lentivirus and siRNA were applied to CAP1 gene knockdown, and plasmids were constructed for CAP1 phosphorylation and de-phosphorylation. Microarray analysis was used for CAP1-associated difference analysis. Both in vitro and in vivo experiments were performed to investigate the roles of CAP1 phosphorylation and de-phosphorylation in lung cancer A549 cells.ResultsCAP1 is a kind of cancer-related protein. Its mRNA was overexpressed in most types of cancer tissues when compared with normal tissues. CAP1 high expression correlated with poor prognosis. Our results showed that serum CAP1 protein concentrations were significantly upregulated in non-small cell lung cancer (NSCLC) patients when compared with the healthy control group, higher serum CAP1 protein concentration correlated with shorter overall survival (OS) in NSCLC patients, and higher pCAP1 and CAP1 protein level were observed in lung cancer patients' tumor tissue compared with adjacent normal tissue. Knockdown CAP1 in A549 cells can inhibit proliferation and migration, and the effect is validated in H1975 cells. It can also lead to an increase ratio of F-actin/G-actin. In addition, phosphorylated S308 and S310 in CAP1 promoted lung cancer cell proliferation, migration, and metastasis both in vitro and in vivo. When de-phosphorylated, these two sites in CAP1 showed the opposite effect. Phosphorylation of CAP1 can promote epithelial-mesenchymal transition (EMT).ConclusionThese findings indicated that CAP1 phosphorylation can promote lung cancer proliferation, migration, and invasion. Phosphorylation sites of CAP1 might be a novel target for lung cancer treatment.

Dataset Information

Phosphorylation of the Cytoskeletal Protein CAP1 Regulates Non-Small Cell Lung Cancer Survival and Proliferation by GSK3?.

Publications

Phosphorylation of the Cytoskeletal Protein CAP1 Regulates Non-Small Cell Lung Cancer Survival and Proliferation by GSK3β.

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