Yanqiu Ou1, Xiaoke Zheng2, Yixing Gao3, Minfeng Shu4, Tiandong Leng4, Yan Li4, Wei Yin5, Wenbo Zhu4, Yijun Huang4, Yuxi Zhou4, Jianjun Tang4, Pengxin Qiu4, Guangmei Yan4, Jun Hu6, Huaizhen Ruan7, Haiyan Hu8. 1. Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou, P.R. China; Guangdong Provincial Cardiovascular Institute, Guangdong General Hospital, Guangdong Provincial Academy of Medical Sciences, Guangzhou, P.R. China. 2. Department of Phathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China; Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou, P.R. China. 3. Department of Neurobiology, College of Basic Medical Science, The Third Military Medical University, Chongqing, P.R. China. 4. Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou, P.R. China. 5. Department of Biochemistry, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou, P.R. China. 6. Department of Microbiology, Zhong-shan School of Medcine, Sun Yat-Sen University, Guangzhou, P.R. China; Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou, P.R. China. Electronic address: hujun@mail.sysu.edu.cn. 7. Department of Neurobiology, College of Basic Medical Science, The Third Military Medical University, Chongqing, P.R. China. Electronic address: Ruanhzruan61@yahoo.com. 8. Department of Pharmaceutics, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, P.R. China. Electronic address: lsshhy@mail.sysu.edu.cn.
Abstract
OBJECTIVE: With the notorious reputation of the vicious invasion, the bladder cancer is the most common malignant tumor of the urinary system. Inhibiting invasion through microtubule dynamics interruption has emerged as an important treatment of bladder cancer. Here we investigated the role of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway in human bladder cancer cells invasion. MATERIALS AND METHODS: With or without the treatment of various cAMP elevators, we assessed invasive and migrated capabilities of T24 and UM-UC-3, two high-grade invasive bladder cancer cell lines, using matrigel transwell inserts assay and scratch wound healing assay. The microtubule (MT) dynamics were examined by immunofluorescence and immunoblotting. Microtubule-Associated Protein 4 (MAP4) was silenced to investigate its role in tumor invasion. We also analyzed gene expression of MAP4 in 34 patients with bladder cancer using immunohistochemical staining assay. The interaction between PKA and MAP4 was examined by co-immunoprecipitation. RESULTS: We used cAMP elevators and small interfering RNA of MAP4 here, found that both of them can potently inhibit the invasion and the migration of bladder cancer cells by disrupting microtubule (MT) cytoskeleton. Consistently, the bladder cancer grade is positively correlated with the protein level of MAP4. Furthermore, we found that cAMP/PKA signaling can disrupt MT cytoskeleton by the phosphorylation of MAP4. CONCLUSION: Our results indicated that the cAMP/PKA signaling pathway might inhibit bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics, which could be exploited for the therapy of invasive bladder cancer.
OBJECTIVE: With the notorious reputation of the vicious invasion, the bladder cancer is the most common malignant tumor of the urinary system. Inhibiting invasion through microtubule dynamics interruption has emerged as an important treatment of bladder cancer. Here we investigated the role of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway in humanbladder cancer cells invasion. MATERIALS AND METHODS: With or without the treatment of various cAMP elevators, we assessed invasive and migrated capabilities of T24 and UM-UC-3, two high-grade invasive bladder cancer cell lines, using matrigel transwell inserts assay and scratch wound healing assay. The microtubule (MT) dynamics were examined by immunofluorescence and immunoblotting. Microtubule-Associated Protein 4 (MAP4) was silenced to investigate its role in tumor invasion. We also analyzed gene expression of MAP4 in 34 patients with bladder cancer using immunohistochemical staining assay. The interaction between PKA and MAP4 was examined by co-immunoprecipitation. RESULTS: We used cAMP elevators and small interfering RNA of MAP4 here, found that both of them can potently inhibit the invasion and the migration of bladder cancer cells by disrupting microtubule (MT) cytoskeleton. Consistently, the bladder cancer grade is positively correlated with the protein level of MAP4. Furthermore, we found that cAMP/PKA signaling can disrupt MT cytoskeleton by the phosphorylation of MAP4. CONCLUSION: Our results indicated that the cAMP/PKA signaling pathway might inhibit bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics, which could be exploited for the therapy of invasive bladder cancer.
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