Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway

Zhu, Wenjing; Shao, Yiye; Yang, Ming; Jia, Mo-Ran; Peng, Yu

doi:10.1016/j.gene.2016.08.049

Cited by 22 publications

(18 citation statements)

References 25 publications

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“…Importantly, we found that delta-secretase is highly phosphorylated in human AD brains, tightly coupled to the activation of its upstream kinase SRPK2 (Figure 2). Moreover, since delta-secretase is greatly upregulated in numerous human cancers (Gawenda et al, 2007; Li et al, 2003; Zhu et al, 2016), one may postulate that active delta-secretase may also be robustly phosphorylated on S226 by SRPK2, mediating cancer cell cycle progression, cell proliferation, and invasion (Andrade et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Wang

Liu

et al. 2017

Molecular Cell

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Summary Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and Tau, controlling the onset of pathogenesis of Alzheimer’s disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that Serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of phosphorylation mimetic (S226D) in young 3XTg mice strongly promoted APP and Tau fragmentation, and facilitated amyloid plaque deposits and neurofibrillary tangles (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreased APP and Tau proteolytic cleavage and attenuated AD pathologies and reversed cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Wang

Liu

et al. 2017

Molecular Cell

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“…Of the 66 RCTs, 1 RCT was C(T)MT versus sham C(T)MT [40], 48 RCTs were C(T)MT versus other active interventions [5, 41–87], and 17 RCTs were C(T)MT plus other active interventions versus same other interventions [88–104] (Tables 1 and 3). …”

Section: Resultsmentioning

confidence: 99%

“…The most common disorders were spine disorders ( n = 42). Among them, 24 studies were for cervical spine [41–62, 88, 89], 14 studies were for thoracolumbar spine [63–70, 90–95], and 4 were classified as others such as scoliosis, sacrococcygeal pain, and ankylosing spondylitis [71, 72, 96, 97]. Studies about extremity diseases/disorders were classified into upper ( n = 13) and lower extremity ( n = 11), including 5 studies about shoulder lesions [5, 73, 74, 98, 99], 8 about arm and hand disorders [75–81, 100], 8 about knee problems [82–85, 101–104], and 2 about leg and foot disorders [86, 87].…”

Section: Resultsmentioning

confidence: 99%

Chuna (or Tuina) Manual Therapy for Musculoskeletal Disorders: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

Lee

Kim

Heo

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Objective To review the literature and systematically evaluate the effectiveness of Chuna (or Tuina) manual therapy (C[T]MT) on pain and function for musculoskeletal disorders. Methods We searched 15 English, Chinese, Japanese, and Korean databases using relevant keywords. All randomized controlled trials (RCTs) of C(T)MT for musculoskeletal disorders were considered, and we limited analyses to studies with a low-risk bias for randomization and/or allocation concealment. Results Sixty-six RCTs with 6,170 participants were included. One sham-controlled RCT showed that C(T)MT relieved pain more effectively than a sham control (SMD −3.09 [−3.59, −2.59]). For active-controlled RCTs, pooled meta-analysis showed that C(T)MT had statistically significant effects on pain reduction, especially compared to traction (P < 0.00001), drugs (P = 0.04), and physical therapies (P < 0.0001). For functional improvement, combined effects of C(T)MT with drugs (P = 0.04) and traction (P = 0.05) also showed similar positive effects. Conclusions This systematic review suggests that C(T)MT is safe and effective for pain reduction and functional improvement for musculoskeletal diseases; however, the evidence for functional improvement was not as strong as for pain reduction. For future studies, high-quality RCTs such as sham-controlled studies with standardized interventions are needed to provide sufficient evidence on the effects of C(T)MT for musculoskeletal diseases. Protocol registration number is CRD42016038307 04/07/2016.

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“…in patients with prostate cancer (17). However, whether AEP participates in pancreatic cancer metastasis remains unknown.…”

Section: Asparaginyl Endopeptidase Enhances Pancreatic Ductal Adenocamentioning

confidence: 99%

Asparaginyl endopeptidase enhances pancreatic ductal adenocarcinoma cell invasion in an exosome-dependent manner and correlates with poor prognosis

et al. 2018

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Pancreatic cancer is one of the most lethal types of cancer; owing to low early detection rates and high metastasis rates, it is associated with an extremely poor prognosis. Therefore, a better understanding of the molecular mechanisms that underlie its metastasis and the identification of potential prognostic biomarkers are urgently required. Although high expression levels of asparaginyl endopeptidase (AEP) have been detected in various types of solid tumor, the expression and functions of AEP in pancreatic carcinomas have yet to be determined. The present study aimed to examine the putative functions of AEP in pancreatic carcinoma. Immunohistochemical analysis revealed that AEP was highly expressed in pancreatic cancer tissues compared with adjacent normal tissues. Patients with high AEP expression exhibited a significantly shorter overall survival time. Results from multivariate Cox regression analysis revealed that AEP was an independent prognostic factor for overall survival. Gain- and loss-of-function experiments demonstrated that knockdown of AEP expression significantly reduced the invasive ability of pancreatic cancer cells, whereas overexpression of AEP increased the invasive ability. In addition, AEP was detected in exosomes that were derived from cultured pancreatic ductal adenocarcinoma cells (PDACs) and in the serum from patients with PDAC. The Matrigel-Transwell invasion assay revealed that exosomes enriched with AEP were able to enhance the invasive ability of PDAC cells, whereas exosomes lacking AEP decreased the invasive ability. Furthermore, results from the present study suggested that AEP may be crucial for activation of the phosphoinositide 3-kinase/RAC‑α serine/threonine-protein kinase signaling pathway in PDAC cells. The present study data indicated that high AEP expression may be important for pancreatic carcinoma progression in an exosome-dependent manner, and that AEP may be an independent indicator of poor prognosis in patients with PDAC and may be a novel prognostic biomarker or therapeutic target in pancreatic carcinoma.

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Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway

Cited by 22 publications

References 25 publications

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Chuna (or Tuina) Manual Therapy for Musculoskeletal Disorders: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

Asparaginyl endopeptidase enhances pancreatic ductal adenocarcinoma cell invasion in an exosome-dependent manner and correlates with poor prognosis

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