Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia

McKenna, Mary K.; Noothi, Sunil K.; Alhakeem, Sara S.; Oben, Karine Z.; Greene, Joseph T.; Mani, Rajeswaran; Perry, Kathryn L.; Collard, James P.; Rivas, Jacqueline R.; Fleischman, Roger A.; Durbin, Eric B.; Byrd, John C.; Wang, Chi; Muthusamy, Natarajan; Bondada, Subbarao

doi:10.1182/blood-2017-10-813931

Cited by 13 publications

(7 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evaluating PAWR expression provided a feasible approach to predict survival and drug responsiveness of ovarian cancer patients by simply performing immunohistochemical staining, which is convenient and cost-effective. Consistent with result for some other tissues [ 13 , 15 ], PAWR was expressed in the cytoplasm in cells of normal fallopian tubes, while there was both cytoplasmic and nuclear expression of PAWR in cancer samples. PAWR can also be secreted spontaneously by normal and cancer cells in culture [ 38 ], providing the possibility of detection by non-invasive liquid biopsy.…”

Section: Discussionsupporting

confidence: 89%

“…3 c). The PTEN/PI3K/AKT signaling pathway, implicated in cell proliferation, apoptosis, metastasis, and chemo-resistance of ovarian cancer, has been reported to correlate with PAWR [ 4 , 15 , 32 ]. Using GEPIA, we found positive correlations between PAWR and the three hub genes of this axis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Endogenous PAWR is essential for apoptosis induction in response to a variety of exogenous insults [ 14 ]. Besides, as a tumor suppressor, PAWR induces apoptosis in a cancer-specific manner [ 9 , 15 ]. PAWR is necessary for PTEN-inducible apoptosis, and inhibition of the PI3K/AKT signaling leads to PAWR-dependent apoptosis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expression of PAWR predicts prognosis of ovarian cancer

Tan

Tao

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

Background Ovarian cancer greatly threatens the general health of women worldwide. Implementation of predictive prognostic biomarkers aids in ovarian cancer management. Methods Using online databases, the general expression profile, target-disease associations, and interaction network of PAWR were explored. To identify the role of PAWR in ovarian cancer, gene correlation analysis, survival analysis, and combined analysis of drug responsiveness and PAWR expression were performed. The predictive prognostic value of PAWR was further validated in clinical samples. Results PAWR was widely expressed in normal and cancer tissues, with decreased expression in ovarian cancer tissues compared with normal tissues. PAWR was associated with various cancers including ovarian cancer. PAWR formed a regulatory network with a group of proteins and correlated with several genes, which were both implicated in ovarian cancer and drug responsiveness. High PAWR expression denoted better survival in ovarian cancer patients (OS: HR = 0.84, P = 0.0077; PFS, HR = 0.86, P = 0.049). Expression of PAWR could predict platinum responsiveness in ovarian cancer and there was a positive correlation between PAWR gene effect and paclitaxel sensitivity. In 12 paired clinical samples, the cancerous tissues exhibited significantly lower PAWR expression than matched normal fallopian tubes. The predictive prognostic value of PAWR was maintained in a cohort of 50 ovarian cancer patients. Conclusions High PAWR expression indicated better survival and higher drug responsiveness in ovarian cancer patients. PAWR could be exploited as a predictive prognostic biomarker in ovarian cancer.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Expression of PAWR predicts prognosis of ovarian cancer

Tan

Tao

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…Here We recently reported that whole-organism knockout Pawr 2/2 3 TCL1 mice display delayed disease development and improved survival compared with Pawr 1/1 3 TCL1 mice. 35 This is ascribed to upregulated p21 expression in leukemic B cells and decreased proliferation resulting from Par-4 knockout. Interestingly, the Par-4 overexpression in leukemic B cells reported here also results in delayed disease progression, suggesting roles for Par-4 in both the leukemia cells and the tumor microenvironment during disease progression.…”

Section: Discussionmentioning

confidence: 99%

Par-4 overexpression impedes leukemogenesis in the Eµ-TCL1 leukemia model through downregulation of NF-κB signaling

Greene¹,

Mani²,

Ramaswamy³

et al. 2019

Blood Advances

Self Cite

View full text Add to dashboard Cite

Prostate apoptosis response 4 (Par-4) is a tumor suppressor that prevents proliferation and induces cell death in several solid tumors. However, its role in B-cell malignancies has not been elucidated. To describe the role of Par-4 in chronic lymphocytic leukemia (CLL) pathogenesis, we developed a B-cell–specific human Par-4–overexpressing mouse model of CLL using the TCL1 leukemia model. While Par-4 transgenic mice did not display any obvious defects in B-cell development or function, disease burden as evidenced by abundance of CD19+CD5+ B cells in the peripheral blood was significantly reduced in Par-4 × TCL1 mice compared with TCL1 littermates. This conferred a survival advantage on the Par-4–overexpressing mice. In addition, a B-cell–specific knockout model displayed the opposite effect, where lack of Par-4 expression resulted in accelerated disease progression and abbreviated survival in the TCL1 model. Histological and flow cytometry–based analysis of spleen and bone marrow upon euthanasia revealed comparable levels of malignant B-cell infiltration in Par-4 × TCL1 and TCL1 individuals, indicating delayed but pathologically normal disease progression in Par-4 × TCL1 mice. In vivo analysis of splenic B-cell proliferation by 5-ethynyl-2-deoxyuridine incorporation indicated >50% decreased expansion of CD19+CD5+ cells in Par-4 × TCL1 mice compared with TCL1 littermates. Moreover, reduced nuclear p65 levels were observed in Par-4 × TCL1 splenic B cells compared with TCL1, suggesting suppressed NF-κB signaling. These findings have identified an in vivo antileukemic role for Par-4 through an NF-κB–dependent mechanism in TCL1-mediated CLL-like disease progression.

show abstract

“…Simultaneously, PAR-4 inhibits the transcriptional activity of the key survival factor NFκB, thus preventing the expression of pro-inflammatory and anti-apoptotic genes [5]. In addition, PAR-4 regulates apoptosis of neurodegenerative diseases [6][7][8]. However, there are few studies on the pro-apoptotic protein PAR-4 in the context of chondrocyte death.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Modulates PAR-4 Expression in an in Vitro Model of Osteoarthritis

Carvalho

Oliveira

Paula

et al. 2022

Braz. arch. biol. technol.

View full text Add to dashboard Cite

Osteoarthritis (OA) encompasses degeneration of articular cartilage, subchondral bone erosions and sclerosis. Chondrocyte apoptosis and an oxygen-deprived microenvironment are essential factors in OA pathogenesis. PAR-4 (Prostate apoptosis response-4) is a pro-apoptotic protein implicated in many pathologies as well as in chondrocyte cell death mechanism. Vitamin D supplementation has been identified as a therapeutic tool for a variety of inflammatory pathologies. In the present manuscript, we investigated whether first, PAR-4 expression is influenced by chondrocytes in a model of OA, in vitro, and second, whether vitamin D modulates PAR-4 expression in the same model. To test our hypothesis, we used the primary culture of murine chondrocytes isolated from the femoral and tibial condyles of wistar rats. The expression of the pro-inflammatory effect interleukin IL-1β was evaluated in the presence and absence of vitamin D. Western blot and immunofluorescence analysis confirmed protein expression. In the normoxia condition, the chondrocytes expressed PAR-4 in the cell nucleus, and in the hypoxic condition, PAR-4 was expressed in the cell cytoplasm. We disclosed that the treatment with Vitamin D decreased PAR-4 (p= 0.0137) and caspase-3 (p= 0.0007) expression. Thus, the results suggested that PAR-4 and caspase-3 proteins could be potential targets for OA.However, we believe that research is needed to identify the mechanisms implicated in the regulation of PAR-4 in OA. HIGHLIGHTS• Chondrocytes express PAR-4 in the nucleus and cytoplasm;• Vitamin D reduces the pro-apoptotic proteins PAR-4 and caspase-3;• PAR-4 and caspase-3 may be potential therapeutic targets for osteoarthritis.

show abstract

Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia

Cited by 13 publications

References 58 publications

Expression of PAWR predicts prognosis of ovarian cancer

Expression of PAWR predicts prognosis of ovarian cancer

Par-4 overexpression impedes leukemogenesis in the Eµ-TCL1 leukemia model through downregulation of NF-κB signaling

Vitamin D Modulates PAR-4 Expression in an in Vitro Model of Osteoarthritis

Contact Info

Product

Resources

About