Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics

Ou, Yanqiu; Zheng, Xiaoke; Gao, Yixing; Shu, Minfeng; Leng, Tiandong; Li, Yan; Yin, Wei; Zhu, Wenbo; Huang, Yijun; Zhou, Yue; Tang, Jianjun; Qiu, Pengxin; Gao, Yan; Hu, Jun; Ruan, Han‐Li; Hu, Haiyan

doi:10.1016/j.urolonc.2013.06.017

Cited by 38 publications

(35 citation statements)

References 27 publications

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“…However, introduction of this mutation leads to increased MAP4 levels, suggesting the C-terminal domain of IFT54 may recruit an additional player required for MAP4 degradation. MAP4 has been shown to be phosphorylated by several microtubule affinity-regulating kinases 24 as well as by PKA, resulting in MAP4 dissociation from the microtubules 35 . Thus, the low PKA activity in mutant cells could also provide an explanation for increased MAP4 levels along the microtubules.…”

Section: Discussionmentioning

confidence: 99%

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

et al. 2015

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Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.

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Section: Discussionmentioning

confidence: 99%

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

et al. 2015

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“…The cAMP/PkA signaling pathway may have an important role in tumor migration. Indeed, activation of the cAMP/PkA pathway inhibits cancer cell migration in various cancers by targeting matrix metalloproteinase (MMP)2, actin, integrin, MMP9 and MMP4 (39)(40)(41)(42). Interestingly, PdE7A contains a PkA pseudosubstrate site within 2 repeated sequences at the N-terminal region of PdE7A.…”

Section: Discussionmentioning

confidence: 99%

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Yamamoto

Nishikawa

Chiyomaru

et al. 2015

International Journal of Oncology

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In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

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“…The cAMP signaling pathway is intimately involved in regulation of cell movement and migration, and although the effects of activation of cAMP signaling on cell migration can be complex, evidence in a number of systems has shown that activation of cAMP signaling leads to inhibition of cell motility, movement, and migration [29,30,42,43]. Indeed, activation of cAMP signaling has already been shown to inhibit migration of a wide range of cells including fibroblasts [2], epithelial cells [3], endothelial cells [4], melanoma cells [5], colon cancer cells [6], pancreatic cancer cells [7,8], bladder cancer cells [9], and cervical cancer cells [10]. The aim of this study was to investigate the activation of cAMP signaling on breast cancer cell motility.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, uncovering a means of inhibiting breast cancer metastasis would provide a significant advance in the treatment of this disease. Stimulation of cAMP signaling has been shown to inhibit migration and motility of a number of cell types, including fibroblasts [2], epithelial cells [3], endothelial cells [4], melanoma cells [5], colon cancer cells [6], pancreatic cancer cells [7,8], bladder cancer cells [9], and cervical cancer cells [10]. Selective elevation of cAMP in breast cancer cells could, therefore, inhibit migration and metastasis of breast cancer cells, and thereby provide an effective means to treat this disease, either alone, or in combination with other established treatments.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of breast cancer cell migration by activation of cAMP signaling

Dong

Claffey

Brocke

et al. 2015

Breast Cancer Res Treat

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Almost all deaths from breast cancer arise from metastasis of the transformed cells to other sites in the body. Hence, uncovering a means of inhibiting breast cancer cell migration would provide a significant advance in the treatment of this disease. Stimulation of the cAMP signaling pathway has been shown to inhibit migration and motility of a number of cell types. A very effective way of selectively stimulating cAMP signaling is through inhibition of cyclic nucleotide phosphodiesterases (PDEs). Therefore, we examined full expression profiles of all known PDE genes at the mRNA and protein levels in four human breast cancer cell lines and eight patients' breast cancer tissues. By these analyses, expression of almost all PDE genes was seen in both cell lines and tissues. In the cell lines, appreciable expression was seen for PDEs 1C, 2A, 3B, 4A, 4B, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 9A, 10A, and 11A. In patients' tissues, appreciable expression was seen for PDEs 1A, 3B, 4A, 4B, 4C, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 8B, and 9A. PDE8A mRNA in particular is prominently expressed in all cell lines and patients' tissue samples examined. We show here that stimulation of cAMP signaling with cAMP analogs, forskolin, and PDE inhibitors, including selective inhibitors of PDE3, PDE4, PDE7, and PDE8, inhibit aggressive triple negative MDA-MB-231 breast cancer cell migration. Under the same conditions, these agents had little effect on breast cancer cell proliferation. This study demonstrates that PDE inhibitors inhibit breast cancer cell migration, and thus may be valuable therapeutic targets for inhibition of breast cancer metastasis. Since PDE8A is expressed in all breast cancer samples, and since dipyridamole, which inhibits PDE8, and PF-04957325, a selective PDE8 inhibitor, both inhibit migration, it suggests that PDE8A may be a valuable novel target for treatment of this disease.

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Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics

Cited by 38 publications

References 27 publications

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Inhibition of breast cancer cell migration by activation of cAMP signaling

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