SENP3 affects the expression of PYCR1 to promote bladder cancer proliferation and EMT transformation by deSUMOylation of STAT3

Li, Zhuo; Liu, Jian; Fu, Huifeng; Li, Yuanwei; Liu, Qiang; Song, Wei; Zeng, Mingqiang

doi:10.18632/aging.204333

Cited by 5 publications

(3 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When STAT3 expression increases, it induces YAP signaling to promote lung tumor cell metastasis [ 53 ]. Nuclear translocation of STAT3 has been reported to be critical for the induction of the epithelial–mesenchymal transition (EMT) and increasing metastasis of bladder cancer, and this is mediated via SENP3 as a regulatory factor [ 54 ]. Circ-BGN and circ-RPPH1 are able to stimulate STAT3 signaling to promote gastric and lung tumor cell progression, respectively [ 55 , 56 ].…”

Section: Stat3 Signaling: An Overviewmentioning

confidence: 99%

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

et al. 2023

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial–mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC. Graphical Abstract

show abstract

Section: Stat3 Signaling: An Overviewmentioning

confidence: 99%

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Evidence for the involvement of PYCR1 in cancer mechanisms is growing rapidly. Several studies have implicated PYCR1 in cancer across various cancer types, including colorectal cancer, − multiple myeloma, kidney cancer, , liver cancer, prostate cancer, − lung cancer, − breast cancer, − and others. ,− Many studies have shown that high PYCR1 expression is associated with tumor aggressiveness and poor patient outcomes. ,− ,,,− Furthermore, the knockdown of the PYCR1 gene or the inhibition of PYCR1 enzyme has been shown to inhibit tumorigenesis in multiple cancer cell lines and in vivo animal models. ,,,− ,,,,,,− Mechanistically, PYCR1 supports cell survival and maintenance in the hypoxic environment of tumor cells when oxygen is not a readily available electron acceptor for NADH. PYCR1 generates NAD + for the TCA cycle in the absence of the electron transport chain, generating proline as a byproduct .…”

Section: Introductionmentioning

confidence: 99%

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography

Meeks,

Ji,

Protopopov

et al. 2024

J. Chem. Inf. Model.

View full text Add to dashboard Cite

The proline biosynthetic enzyme Δ 1 -pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) is one of the most consistently upregulated enzymes across multiple cancer types and central to the metabolic rewiring of cancer cells. Herein, we describe a fragment-based, structure-first approach to the discovery of PYCR1 inhibitors. Thirty-seven fragment-like carboxylic acids in the molecular weight range of 143−289 Da were selected from docking and then screened using X-ray crystallography as the primary assay. Strong electron density was observed for eight compounds, corresponding to a crystallographic hit rate of 22%. The fragments are novel compared to existing proline analog inhibitors in that they block both the P5C substrate pocket and the NAD(P)H binding site. Four hits showed inhibition of PYCR1 in kinetic assays, and one has lower apparent IC 50 than the current best proline analog inhibitor. These results show proof-of-concept for our inhibitor discovery approach and provide a basis for fragment-to-lead optimization.

show abstract

“…Numerous correlative and mechanistic links of PYCR1 to cancer progression and metastasis have been reported. Many studies have shown that high PYCR1 expression is associated with tumor aggressiveness and poor patient outcomes (Alaqbi et al, 2022; Ding et al, 2017, 2020; Du et al, 2021; Li, Xu, et al, 2022; Li, Liu, et al, 2022; Liu et al, 2021; Oudaert et al, 2022; Shao et al, 2022; Shenoy et al, 2020; Weijin et al, 2019; Xiao et al, 2020; Xu et al, 2021; Zhang et al, 2021), and the knockdown of the PYCR1 gene or the inhibition of PYCR1 enzyme has been shown to inhibit tumorigenesis in cancer cell lines and animal models of cancer (Alaqbi et al, 2022; Cai et al, 2018; Christensen et al, 2020; Ding et al, 2020; Du et al, 2021; Elia et al, 2017; Gao et al, 2020; Li et al, 2023; Li, Liu, et al, 2022; Li, Xu, et al, 2022; Sang et al, 2019; Shenoy et al, 2020; Xiao et al, 2020; Xu et al, 2021; Yan et al, 2019; Zeng et al, 2017; Zhuang et al, 2019). The production of proline via PYCR1 may be an indicator of cancer stem‐like cells, which can survive chemotherapy treatments and lead to relapse in cancer patients (Sharif et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Screening a knowledge‐based library of low molecular weight compounds against the proline biosynthetic enzyme 1‐pyrroline‐5‐carboxylate 1 (PYCR1)

Meeks,

Bogner,

Tanner

2024

Protein Science

View full text Add to dashboard Cite

AbstractΔ1‐pyrroline‐5‐carboxylate reductase isoform 1 (PYCR1) is the last enzyme of proline biosynthesis and catalyzes the NAD(P)H‐dependent reduction of Δ1‐pyrroline‐5‐carboxylate to L‐proline. High PYCR1 gene expression is observed in many cancers and linked to poor patient outcomes and tumor aggressiveness. The knockdown of the PYCR1 gene or the inhibition of PYCR1 enzyme has been shown to inhibit tumorigenesis in cancer cells and animal models of cancer, motivating inhibitor discovery. We screened a library of 71 low molecular weight compounds (average MW of 131 Da) against PYCR1 using an enzyme activity assay. Hit compounds were validated with X‐ray crystallography and kinetic assays to determine affinity parameters. The library was counter‐screened against human Δ1‐pyrroline‐5‐carboxylate reductase isoform 3 and proline dehydrogenase (PRODH) to assess specificity/promiscuity. Twelve PYCR1 and one PRODH inhibitor crystal structures were determined. Three compounds inhibit PYCR1 with competitive inhibition parameter of 100 μM or lower. Among these, (S)‐tetrahydro‐2H‐pyran‐2‐carboxylic acid (70 μM) has higher affinity than the current best tool compound N‐formyl‐l‐proline, is 30 times more specific for PYCR1 over human Δ1‐pyrroline‐5‐carboxylate reductase isoform 3, and negligibly inhibits PRODH. Structure‐affinity relationships suggest that hydrogen bonding of the heteroatom of this compound is important for binding to PYCR1. The structures of PYCR1 and PRODH complexed with 1‐hydroxyethane‐1‐sulfonate demonstrate that the sulfonate group is a suitable replacement for the carboxylate anchor. This result suggests that the exploration of carboxylic acid isosteres may be a promising strategy for discovering new classes of PYCR1 and PRODH inhibitors. The structure of PYCR1 complexed with l‐pipecolate and NADH supports the hypothesis that PYCR1 has an alternative function in lysine metabolism.

show abstract

SENP3 affects the expression of PYCR1 to promote bladder cancer proliferation and EMT transformation by deSUMOylation of STAT3

Cited by 5 publications

References 45 publications

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography

Screening a knowledge‐based library of low molecular weight compounds against the proline biosynthetic enzyme 1‐pyrroline‐5‐carboxylate 1 (PYCR1)

Contact Info

Product

Resources

About