Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma

McKee, Chad M.; Xu, Danmei; Cao, Yuze; Kabraji, Sheheryar; Allen, Danny; Kersemans, Veerle; Beech, John S.; Smart, Sean; Hamdy, Freddie C.; Ishkanian, Adrian; Sykes, Jenna; Pintile, Melania; Milosevic, Michael; Kwast, Theodorus H. van der; Zafarana, Gaetano; Ramnarine, Varune Rohan; Jurišica, Igor; Mallof, Chad; Lam, Wan L.; Bristow, Robert G.; Muschel, Ruth J.

doi:10.1172/jci59348

Cited by 42 publications

(57 citation statements)

References 63 publications

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“…Our observations that PN1 negatively regulates FGF signals and stabilizes Sdc4 protein in an HtrA1-dependent manner are consistent with a possible indirect inhibition of zygotic Wnt/β-catenin signaling by PN1. In mouse, PN1 inhibits Shh signaling in the postnatal cerebellum and in prostate cancer (Vaillant et al, 2007;McKee et al, 2012). However, Hh antagonism is unlikely to explain the PN1 activities described here because Hh signals do not induce mesoderm and -similar to PN1 -inhibit neuronal differentiation and promote anterior development in the early Xenopus embryo (Lai et al, 1995;Franco et al, 1999;Min et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

et al. 2015

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Germ layer formation and primary axis development rely on Fibroblast growth factors (FGFs). In Xenopus, the secreted serine protease HtrA1 induces mesoderm and posterior trunk/tail structures by facilitating the spread of FGF signals. Here, we show that the serpin Protease nexin-1 (PN1) is transcriptionally activated by FGF signals, suppresses mesoderm and promotes head development in mRNAinjected embryos. An antisense morpholino oligonucleotide against PN1 has the opposite effect and inhibits ectodermal fate. However, ectoderm and anterior head structures can be restored in PN1-depleted embryos when HtrA1 and FGF receptor activities are diminished, indicating that FGF signals negatively regulate their formation. We show that PN1 binds to and inhibits HtrA1, prevents degradation of the proteoglycan Syndecan 4 and restricts paracrine FGF/Erk signaling. Our data suggest that PN1 is a negative-feedback regulator of FGF signaling and has important roles in ectoderm and head development.

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Section: Discussionmentioning

confidence: 92%

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

et al. 2015

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“…In contrast, we previously found that SERPINE2 presents in both normal and benign prostate hypertrophy tissues while its level reduced in prostate carcinoma with a higher Gleason score (21). The SERPINE2-mediated inhibition of uPA serves to prevent prostate cell invasion and metastasis, whereas MMP9 upregulates uPA and facilitates tumor cell invasion through cleavage of SERPINE2 (22).…”

Section: Introductionmentioning

confidence: 85%

“…5). SERPINE2 inhibits Hedgehog signaling by down-regulating SHH and its down-stream targets including PTCH1, GLI1 and CCND1, thus inhibiting proliferation of prostate cancer cells and conferring protective activity (21). Previously, we found that SERPINE2 has anti-angiogenesis activity in human prostate cancer.…”

Section: Serpine2 Expression Differs In Most Tumors and Their Countermentioning

confidence: 95%

Expression pattern of human SERPINE2 in a variety of human tumors

Yang

Xin

et al. 2018

Oncol Lett

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Abstract. Serine proteinase inhibitor, clade E member 2 (SERPINE2), also known as protease nexin-1 (PN-1), is a member of the serpin family. Despite several reported roles of SERPINE2 in tumor development the histological distribution of SERPINE2 and its expression levels in a large variety of tumors remains unclear. Through expressed sequence tag database analysis, immunohistochemical staining of tissue microarrays and a literature review, it was revealed that SERPINE2 expression varied according to growth stages and tissue types. SERPINE2 is differentially expressed in a number of tumors and their normal tissue counterparts. SERPINE2 is identified most abundantly in adenocarcinomas. SERPINE2 serves diverse roles in a variety of tumors and therefore may serve as a promising biomarker for tumor diagnosis and prognosis.

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“…The level of PN1 itself is negatively regulated by matrix metalloproteinase 9 (MMP9), which is frequently up-regulated in human malignancies and associated with tumor progression, invasion and metastasis. Thus, increased levels of MMP9 inhibit PN1 function in PCa, thereby leading to an elevated Hh signaling activity and hence PCa progression [66]. …”

Section: Hedgehog Signalingmentioning

confidence: 99%

“…The most extensively studied compound is cyclopamine, a naturally occurring molecule derived from the plant Veratrum californicum. Cyclopamine inhibits Hh signaling by acting on Smo with an EC50 of approximately 300 nM [65,66]. Preclinical studies in MB and BCC with cyclopamine were very promising, but this compound failed further development in clinical trials due to its poor pharmacokinetic characteristics (highly insoluble in water, poor chemical stability in acidic conditions), low potency and associated toxicity [67,68].…”

Section: Therapeutic Application Of Hedgehog Inhibitionmentioning

confidence: 99%

Hedgehog Signaling in Prostate Cancer and Its Therapeutic Implication

Gonnissen

Isebaert

Haustermans

2013

IJMS

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Activation of Hedgehog (Hh) signaling is implicated in the development and progression of several tumor types, including prostate cancer, which is still the most common non-skin malignancy and the third leading cause of cancer-related mortality in men in industrialized countries worldwide. Several studies have indicated that the Hh pathway plays a crucial role in the development as well as in the progression of this disease to more aggressive and even therapy-resistant disease states. Moreover, preclinical data have shown that inhibition of Hh signaling has the potential to reduce prostate cancer invasiveness and metastatic potential. Clinical trials investigating the benefit of Hh inhibitors in patients with prostate cancer have recently been initiated. However, acquired drug resistance has already been observed in other tumor types after long-term Hh inhibition. Therefore, combining Hh inhibitors with ionizing radiation, chemotherapy or other molecular targeted agents could represent an alternative therapeutic strategy. In this review, we will highlight the role of Hh signaling in the development and progression of prostate cancer and summarize the different therapeutic applications of Hedgehog inhibition.

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Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma

Cited by 42 publications

References 63 publications

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

Expression pattern of human SERPINE2 in a variety of human tumors

Hedgehog Signaling in Prostate Cancer and Its Therapeutic Implication

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