DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis

Zhou, Jiancheng; Ning, Zhongyun; Wang, B.; Yun, Eun Joo; Zhang, Tianlong; Pong, Rey-Chen; Fazli, Ladan; Gleave, Martin; Zeng, Jin; Fan, Jinhai; Wang, X.; Li, L.; Hsieh, Jer Tsong; He, Dalin; Wu, Kaijie

doi:10.1038/cddis.2015.289

Cited by 26 publications

(27 citation statements)

References 36 publications

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“…This result is consistent with the reduction in the number of epithelial cells in the prostate after glandular involution in castrated rats. Although an increase in STAT signaling during PCa progression of androgen-independent tumors has been demonstrated (Wertz 2009;Zhou et al 2015), we believe that, in contrast to androgen-independent cells, in the normal prostate, this effect does not occur, mostly because of the massive epithelial cell death after castration. In the T3 group, we observed the initiation of glandular recovery, however, without an increase of PRLR expression.…”

Section: Discussionmentioning

confidence: 77%

The prostate response to prolactin modulation in adult castrated rats subjected to testosterone replacement

et al. 2017

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Despite the androgenic dependence, other hormones, growth factors, and cytokines are necessary to support prostatic growth and maintain the glandular structure; among them, prolactin is a non-steroidal hormone secreted mainly by the pituitary gland. However, extra-pituitary expression of prolactin, such as in the prostate, has also been demonstrated, highlighting the paracrine and autocrine actions of prolactin within the prostate. Here, we investigated whether prolactin modulation alters ventral prostate (VP) morphophysiology in adult castrated rats. Sprague Dawley rats were castrated and after 21 days, divided into ten experimental groups (n = 6/group): castrated control: castrated animals that did not receive treatment; castrated+testosterone: castrated animals that received T (4 mg/kg/day); castrated+PRL (PRL): castrated animals receiving prolactin (0.3 mg/kg/day); castrated+T+PRL: castrated animals that received a combination of testosterone and prolactin; and castrated+bromocriptine (BR): castrated animals that received bromocriptine (0.4 mg/kg/day). The control group included intact animals. The animals were treated for 3 or 10 consecutive days. At the end of experimental period, the animals were euthanized, and the blood and VP lobes were collected and analyzed by different methods. The main findings were that the administration of prolactin to castrated rats did not exert anabolic effects on the VP. Although we observed activation of downstream prolactin signaling after prolactin administration, this was not enough to overcome the prostatic androgen deficiency. Likewise, there was no additional glandular involution in the castrated group treated with bromocriptine. We concluded that despite stimulating the downstream signaling pathway, exogenous prolactin does not act on VP in the absence or presence of high levels of testosterone.

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Section: Discussionmentioning

confidence: 77%

The prostate response to prolactin modulation in adult castrated rats subjected to testosterone replacement

et al. 2017

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“…35 In prostate cancer cells, DAB2IP was found to directly bind STAT3, suppressing transactivation and expression of the anti-apoptotic target survivin. 36 It is highly plausible that DAB2IP can negatively regulate activation of STAT3 in other cell types, with implications for additional tumor conditions.…”

Section: Ask1-jnkmentioning

confidence: 99%

“…In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K-AKT phosphorylation and activation. 33 DAB2IP also binds directly STAT3, inhibiting its transactivating function 36 Tumor suppressor DAB2IP in cancer A Bellazzo et al and expression of EMT and stem cell markers. 45 Accordingly, in CRC patients reduced DAB2IP levels correlate with increased number of CD133-positive cells (stem cell marker) and faster tumor progression.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

“…58 Similarly, by augmenting STAT3 activation and survivin expression, loss of DAB2IP facilitates survival of prostate cancer cells after androgen deprivation therapy. 36 Very recently, it has been reported that DAB2IP depletion causes defects in microtubule-kinetochore attachment, increasing the frequency of aberrant mitoses in prostate cancer cell lines. In line with these observations, MEFs from DAB2IP KO mice display aneuploidy.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

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Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

2016

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One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

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“…Furthermore, DAB2IP is recognized as a direct downstream target of miR-889 in esophageal squamous cell carcinomas (10). In prostate cancer, loss of DAB2IP facilitates the metastasis and epithelial-mesenchymal transition (EMT) process of cancer cells (11), and DAB2IP silencing inhibits androgen deprivation therapy-induced apoptosis via targeting STAT3 signaling (12). Furthermore, DAB2IP deficiency promotes the growth of renal cell cancer (RCC) and leads to the resistance of mTOR-targeted therapies in metastatic RCC (13,14).…”

Section: Introductionmentioning

confidence: 99%

DOC-2/DAB2 interactive protein regulates proliferation and mobility of nasopharyngeal carcinoma cells by targeting PI3K/Akt pathway

Wang

2017

Oncology Reports

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Tumor suppressors are a group of important inverse regulators for carcinogenesis in human cancers including nasopharyngeal carcinoma (NPC). DOC-2/DAB2 interactive protein (DAB2IP) has been found to be a novel tumor suppressor in malignancies. However, the expression and biological function of DAB2IP in NPC have not been previously reported. This study found that the levels of DAB2IP were decreased in NPC tissues compared to non-cancerous nasopharyngeal epithelium tissues. In addition, downregulation of DAB2IP mRNA was confirmed by qRT-PCR in NPC cell lines as compared with a human immortalized nasopharyngeal epithelial cell line NP69. The reduced expression of DAB2IP was significantly correlated with lymph node metastasis and advanced clinical stage. DAB2IP low expressing NPC patients showed a notable reduced overall survival and disease-free survival. Functionally, DAB2IP restoration prohibited cell proliferation, colony formation, migration and invasion in both 5-8F and CNE-2 cells. Moreover, DAB2IP overexpression restrained the subcutaneous growth and lung metastasis of NPC cells in nude mice. Mechanically, DAB2IP overexpression repressed the activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and subsequently reduced the expression of its downstream targets including cyclin D1 and matrix metallopeptidase 7 (MMP7), which were identified as critical regulators for growth and metastasis of NPC. The Akt inhibitor MK-2206 showed similar effects to DAB2IP overexpression on growth and metastasis of 5-8F cells. Thus, DAB2IP suppresses growth and metastasis of NPC probably by targeting PI3K/Akt pathway, and may act as a hopeful therapeutic target for NPC.

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DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis

Cited by 26 publications

References 36 publications

The prostate response to prolactin modulation in adult castrated rats subjected to testosterone replacement

The prostate response to prolactin modulation in adult castrated rats subjected to testosterone replacement

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

DOC-2/DAB2 interactive protein regulates proliferation and mobility of nasopharyngeal carcinoma cells by targeting PI3K/Akt pathway

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