Proteomic profiling of
            FBXW7
            ‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Abstract Cancer-associated fibroblasts (CAFs) tend to have tumor-promoting capacity, and can provide therapeutic targets. Even without cancer cells, CAF phenotypes are stably maintained, and DNA methylation and H3K27me3 changes have been shown to be involved. Here, we searched for a potential therapeutic target in primary CAFs from gastric cancer and a mechanism for its dysregulation. Expression microarray using eight CAFs and seven non-CAFs (NCAFs) revealed that serum amyloid A1 (SAA1), which encodes an acute phase secreted protein, was second most upregulated in CAFs, following IGF2. Conditioned medium (CM) derived from SAA1-overexpressing NCAFs was shown to increase migration of gastric cancer cells compared to that from control NCAFs, and its tumor-promoting effect was comparable to that of CM from CAFs. In addition, increased migration of cancer cells by CM from CAFs was mostly canceled with CM from CAFs with SAA1 knockdown. Chromatin immunoprecipitation (ChIP)-quantitative PCR showed that CAFs had higher levels of H3K27ac, an active enhancer mark, in the promoter and the two far upstream regions of SAA1 than NCAFs. Also, BET bromodomain inhibitors, JQ1 and mivebresib, decreased SAA1 expression and tumor-promoting effects in CAFs, suggesting SAA1 upregulation by enhancer activation in CAFs. Our present data showed that SAA1 is a candidate therapeutic target from gastric CAFs and indicated that increased enhancer acetylation is important for its overexpression.

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The Role of Cellular Prion Protein in Cancer Biology: A Potential Therapeutic Target

Frontiers in Oncology ◽

10.3389/fonc.2021.742949 ◽

2021 ◽

Vol 11 ◽

Author(s):

Manqiu Ding ◽

Yongqiang Chen ◽

Yue Lang ◽

Li Cui

Keyword(s):

Stem Cells ◽

Nervous System ◽

Cell Survival ◽

Cancer Cells ◽

Prion Protein ◽

Therapeutic Target ◽

Cancer Biology ◽

Cellular Prion Protein ◽

Potential Therapeutic Target

Prion protein has two isoforms including cellular prion protein (PrPC) and scrapie prion protein (PrPSc). PrPSc is the pathological aggregated form of prion protein and it plays an important role in neurodegenerative diseases. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein that can attach to a membrane. Its expression begins at embryogenesis and reaches the highest level in adulthood. PrPC is expressed in the neurons of the nervous system as well as other peripheral organs. Studies in recent years have disclosed the involvement of PrPC in various aspects of cancer biology. In this review, we provide an overview of the current understanding of the roles of PrPC in proliferation, cell survival, invasion/metastasis, and stem cells of cancer cells, as well as its role as a potential therapeutic target.

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Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-04201-w ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Xiao-ren Zhu ◽

Shi-qing Peng ◽

Le Wang ◽

Xiao-yu Chen ◽

Chun-xia Feng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Phosphoenolpyruvate Carboxykinase ◽

Human Pancreatic Cancer ◽

Migration And Invasion ◽

Potential Therapeutic Target ◽

Protein Levels ◽

Pancreatic Cancer Cells

AbstractPancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.

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TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

Oncogene ◽

10.1038/s41388-018-0470-2 ◽

2018 ◽

Vol 38 (6) ◽

pp. 852-867 ◽

Cited By ~ 14

Author(s):

Stephanie E. van Gijn ◽

Elles Wierenga ◽

Nathalie van den Tempel ◽

Yannick P. Kok ◽

Anne Margriet Heijink ◽

...

Keyword(s):

Cancer Cells ◽

Therapeutic Target ◽

Aurora Kinase ◽

Potential Therapeutic Target ◽

Aurora Kinase A ◽

Kinase A

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LAMC1 is a prognostic factor and a potential therapeutic target in endometrial cancer

Journal of Gynecologic Oncology ◽

10.3802/jgo.2020.31.e11 ◽

2020 ◽

Vol 31 (2) ◽

Cited By ~ 2

Author(s):

Haruko Kunitomi ◽

Yusuke Kobayashi ◽

Ren-Chin Wu ◽

Takashi Takeda ◽

Eiichiro Tominaga ◽

...

Keyword(s):

Endometrial Cancer ◽

Prognostic Factor ◽

Therapeutic Target ◽

Potential Therapeutic Target

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Plasma membrane proteomics identifies bone marrow stromal antigen 2 as a potential therapeutic target in endometrial cancer

International Journal of Cancer ◽

10.1002/ijc.27679 ◽

2012 ◽

Vol 132 (2) ◽

pp. 472-484 ◽

Cited By ~ 36

Author(s):

Takuhei Yokoyama ◽

Takayuki Enomoto ◽

Satoshi Serada ◽

Akiko Morimoto ◽

Shinya Matsuzaki ◽

...

Keyword(s):

Bone Marrow ◽

Endometrial Cancer ◽

Plasma Membrane ◽

Therapeutic Target ◽

Potential Therapeutic Target ◽

Membrane Proteomics

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Role of GADD45α as a potential therapeutic target for prostate cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10566 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10566-10566

Author(s):

R. Singal ◽

K. Ramachandran ◽

G. Gopisetty ◽

L. Navarro ◽

E. Gordian ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Therapeutic Target ◽

Recombinant Expression ◽

Proximal Promoter ◽

Lncap Cells ◽

Potential Therapeutic Target ◽

Du145 Cells ◽

Docetaxel Chemotherapy

10566 Background: Defects in the apoptotic pathway contribute to uncontrolled cell proliferation of cancer cells and confer resistance to chemotherapeutic drugs. Understanding the mechanisms of deregulation of apoptosis related genes would enable targeted treatment methods to improve the efficacy of chemotherapy. Growth Arrest and DNA Damage inducible, alpha (GADD45a) mediates cytotoxicity of docetaxel chemotherapy. We examined the mechanism of regulation of GADD45a in prostate cancer cells and the effect of its upregulation on sensitivity to docetaxel chemotherapy. Methods: Levels of GADD45a in Du145, LNCaP and PC3 were analyzed by real time reverse transcriptase PCR and western blotting. DNA methylation was studied by bisulfite sequencing. Chromatin immunoprecipitation was used to study interaction of methyl binding proteins to GADD45 5’ sequence. Cytotoxicity after drug treatment was measured by MTT cell proliferation assay. Apoptosis assays were done by Annexin V/propidium iodide staining followed by flow cytometry. Results: Levels of expression of GADD45a in Du145 and LNCaP cells were lower than that in PC3. A 4 CpG region upstream of the proximal promoter region was methylated in Du145 and LNCaP cells. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyl transferase (DNMT) inhibitors such as 5- Azacytidine or 5- Aza deoxycytidine leading to reactivation of GADD45a expression in these cells. This region was also frequently methylated in prostate cancer tissues. Methyl binding protein, MeCP2 was associated with the methylated 4 CpGs in Du145 and knock down of MeCP2 by transfection of MeCP2 siRNA vector in Du145 cells (Du145-MeCP2-ve) led to increased expression of GADD45a, without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by upregulation of GADD45a in Du145 cells by (a) recombinant expression of GADD45a (b) downregulation of MeCP2 and (c) pretreatment with 5-Azacytidine. Conclusions: GADD45a is frequently deregulated in prostate cancer by methylation of 5’ 4 CpG region and is a potential therapeutic target for treatment of prostate cancer. [Table: see text]

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