Plexin-B1 signalling promotes androgen receptor translocation to the nucleus

Williamson, Magali; Winter, Patricia de; Masters, J. R. W.

doi:10.1038/onc.2015.160

Cited by 38 publications

(24 citation statements)

References 42 publications

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“…In vitro assays also demonstrated NSCLC cell lines H1299, HCC827, A549 and H1975 had a high level of sema4D expression, however, they have various ability to form vascular‐like channels in matrigel. As previous studies reported, sema4D plays important roles in diverse physiological processes such as tumor cell proliferation, survival, migration, invasion, tumor angiogenesis and immunity, and this may be the reason why NSCLC tissues and cell lines had a high level of sema4D. On the other hand, VM channels were all detected in Sema4D‐positive NSCLC tissues and in none of Sema4D‐negative samples in our study (Fig.…”

Section: Discussionsupporting

confidence: 66%

“…The high‐affinity Sema4D receptor plexinB1 is mainly expressed in endothelial and epithelial cells . The role of Sema4D/plexinB1 signaling in regulating tumor angiogenesis has been widely studied . Our studies revealed that the regulatory effect of Sema4D on VM formation in NSCLC cells also relied on binding with plexinB1 (Figs.…”

Section: Discussionmentioning

confidence: 75%

“…Sema4D has been reported to be highly expressed in several types of human cancers, such as prostate, colon, breast, lung, head and neck carcinomas . By cooperating with its high‐affinity receptor plexinB1, Sema4D plays important roles in tumor cell proliferation, survival, migration, invasion, tumor angiogenesis and immunity . PlexinB1 is a transmembrane protein, which contains a ligand‐binding domain (Sema) in its extracellular region and a PDZ‐binding motif in the intracellular portion .…”

Section: Introductionmentioning

confidence: 99%

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The role of sema4D in vasculogenic mimicry formation in non‐small cell lung cancer and the underlying mechanisms

Xia

Cai

Fan

et al. 2018

Intl Journal of Cancer

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Vasculogenic mimicry (VM) is a special vascular pattern in malignant tumors, which is composed of highly aggressive tumor cells. This tumor cell-mediated blood supply pattern is closely associated with a poor prognosis in cancer patients. The interaction of axon guidance factor Sema4D and its high affinity receptor plexinB1 could activate small GTPase RhoA and its downstream ROCKs; this process has an active role in the migration of endothelial cells and tumor angiogenesis. Here, we have begun to uncover the role of this pathway in VM formation in non-small cell lung cancer (NSCLC). First, we confirmed this special form of vasculature in NSCLC tissues and found the existence of VM channels in tumor tissues was correlated with Sema4D expression. Further, we found that inhibition of Sema4D in the human NSCLC cells H1299 and HCC827 reduces VM formation both in vitro and in vivo. Moreover, we demonstrated that downregulating the expression of plexinB1 by siRNA expressing vectors and inhibiting the RhoA/ROCK signaling pathway using fasudil can reduce VM formation of H1299 and HCC827 cells. Finally, we found that suppression of Sema4D leads to less stress fibers and depleted the motility of H1299 and HCC827 cells. Collectively, our study implicates Sema4D plays an important role in the process of VM formation in NSCLC through activating the RhoA/ROCK pathway and regulating tumor cell plasticity and migration. Modulation of the Sema4D/ plexinB1 and downstream RhoA/ROCK pathway may prevent the tumor blood supply through the VM pattern, which may eventually halt growth and metastasis of NSCLC. Role of sema4D in vasculogenic mimicry formationInt.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of sema4D in vasculogenic mimicry formation in non‐small cell lung cancer and the underlying mechanisms

Xia

Cai

Fan

et al. 2018

Intl Journal of Cancer

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“…However we have detected the presence of a neural-derived regulatory protein, Sema3C (data not shown), that may indicate the inclusion of a neural tissue extract. Given reports that PCa cells express a Semaphorin receptor (Plexin B1) and are influenced by Semaphorins [35, 36], perhaps Semaphorin signaling plays some role in the model we described.…”

Section: Discussionmentioning

confidence: 95%

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance

et al. 2017

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Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.

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“…Indeed, Yu et al 's results also identify ARBSs in nearly all other class 3 semaphorins, most notably three ARBSs in another class 3 semaphorin with well-documented tumor-promoting activity, SEMA3E. Conversely, receptors to semaphorins have been shown to promote AR activity [84]. …”

Section: Discussionmentioning

confidence: 99%

Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner

et al. 2016

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The androgen receptor (AR) is a member of the nuclear receptor superfamily of transcription factors and is central to prostate cancer (PCa) progression. Ligand-activated AR engages androgen response elements (AREs) at androgen-responsive genes to drive the expression of gene batteries involved in cell proliferation and cell fate. Understanding the transcriptional targets of the AR has become critical in apprehending the mechanisms driving treatment-resistant stages of PCa. Although AR transcription regulation has been extensively studied, the signaling networks downstream of AR are incompletely described. Semaphorin 3C (SEMA3C) is a secreted signaling protein with roles in nervous system and cardiac development but can also drive cellular growth and invasive characteristics in multiple cancers including PCa. Despite numerous findings that implicate SEMA3C in cancer progression, regulatory mechanisms governing its expression remain largely unknown. Here we identify and characterize an androgen response element within the SEMA3C locus. Using the AR-positive LNCaP PCa cell line, we show that SEMA3C expression is driven by AR through this element and that AR-mediated expression of SEMA3C is dependent on the transcription factor GATA2. SEMA3C has been shown to promote cellular growth in certain cell types so implicit to our findings is the discovery of direct regulation of a growth factor by AR. We also show that FOXA1 is a negative regulator of SEMA3C. These findings identify SEMA3C as a novel target of AR, GATA2, and FOXA1 and expand our understanding of semaphorin signaling and cancer biology.

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Plexin-B1 signalling promotes androgen receptor translocation to the nucleus

Cited by 38 publications

References 42 publications

The role of sema4D in vasculogenic mimicry formation in non‐small cell lung cancer and the underlying mechanisms

The role of sema4D in vasculogenic mimicry formation in non‐small cell lung cancer and the underlying mechanisms

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance

Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner

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