Post-translational Regulation of the Cleaved Fragment of Par-4 in Ovarian and Endometrial Cancer Cells

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 May 14

PMID 27175591

Citations 7

Authors

Kevin Brasseur

Francois Fabi

Pascal Adam

Sophie Parent

Laurent Lessard

Eric Asselin

Affiliations

Soon will be listed here.

Abstract

We recently reported the caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kDa cleaved-Par-4 (cl-Par-4) fragment and we investigated in the present study the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines.Cl-Par-4 protein was weakly express in all stable clones despite constitutive expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure might in fact protect cl-Par-4 from proteasome-dependent degradation. PI3K and MAPK pathways were also implicated as evidenced by an increase of cl-Par-4 in the presence of PI3K inhibitors and a decrease using MAPK inhibitors. Finally using bioinformatics resources, we found diverse datasets showing similar results to those we observed with the proteasome and cl-Par-4 further supporting our data.These new findings add to the complex mechanisms regulating Par-4 expression and activity, and justify further studies addressing the biological significance of this phenomenon in gynaecological cancer cells.

Citing Articles

Prostate apoptosis response-4 and tumor suppression: it's not just about apoptosis anymore.

Cheratta A, Thayyullathil F, Pallichankandy S, Subburayan K, Alakkal A, Galadari S Cell Death Dis. 2021; 12(1):47.

PMID: 33414404 PMC: 7790818. DOI: 10.1038/s41419-020-03292-1.

Pharmacologic inhibition of Akt in combination with chemotherapeutic agents effectively induces apoptosis in ovarian and endometrial cancer cell lines.

Fabi F, Adam P, Parent S, Tardif L, Cadrin M, Asselin E Mol Oncol. 2020; 15(8):2106-2119.

PMID: 33338300 PMC: 8334290. DOI: 10.1002/1878-0261.12888.

pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain.

Clark A, Ponniah K, Warden M, Raitt E, Yawn A, Pascal S Biomolecules. 2018; 8(4).

PMID: 30518159 PMC: 6316887. DOI: 10.3390/biom8040162.

Modeling Endometrial Cancer: Past, Present, and Future.

Van Nyen T, Moiola C, Colas E, Annibali D, Amant F Int J Mol Sci. 2018; 19(8).

PMID: 30096949 PMC: 6121384. DOI: 10.3390/ijms19082348.

Chemoresistance and targeted therapies in ovarian and endometrial cancers.

Brasseur K, Gevry N, Asselin E Oncotarget. 2016; 8(3):4008-4042.

PMID: 28008141 PMC: 5354810. DOI: 10.18632/oncotarget.14021.

References

Johnstone R, See R, Sells S, Wang J, Muthukkumar S, Englert C . A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. Mol Cell Biol. 1996; 16(12):6945-56. PMC: 231698. DOI: 10.1128/MCB.16.12.6945. View

Gurumurthy S, Goswami A, Vasudevan K, Rangnekar V . Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Mol Cell Biol. 2005; 25(3):1146-61. PMC: 544017. DOI: 10.1128/MCB.25.3.1146-1161.2005. View

Chanvorachote P, Nimmannit U, Stehlik C, Wang L, Jiang B, Ongpipatanakul B . Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination. Cancer Res. 2006; 66(12):6353-60. DOI: 10.1158/0008-5472.CAN-05-4533. View

Goswami A, Burikhanov R, de Thonel A, Fujita N, Goswami M, Zhao Y . Binding and phosphorylation of par-4 by akt is essential for cancer cell survival. Mol Cell. 2005; 20(1):33-44. DOI: 10.1016/j.molcel.2005.08.016. View

Shrestha-Bhattarai T, Rangnekar V . Cancer-selective apoptotic effects of extracellular and intracellular Par-4. Oncogene. 2010; 29(27):3873-80. PMC: 2900490. DOI: 10.1038/onc.2010.141. View

Chen X, Sahasrabuddhe A, Szankasi P, Chung F, Basrur V, Rangnekar V . Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell Death Differ. 2014; 21(10):1535-45. PMC: 4158693. DOI: 10.1038/cdd.2014.92. View

Guo R, Wei L, Tu Z, Sun P, Wang J, Zhao D . 17 beta-estradiol activates PI3K/Akt signaling pathway by estrogen receptor (ER)-dependent and ER-independent mechanisms in endometrial cancer cells. J Steroid Biochem Mol Biol. 2006; 99(1):9-18. DOI: 10.1016/j.jsbmb.2005.11.013. View

Chen X, Qiu J, Shi S, Suo S, Huang S, Liang R . Incorporating key position and amino acid residue features to identify general and species-specific Ubiquitin conjugation sites. Bioinformatics. 2013; 29(13):1614-22. DOI: 10.1093/bioinformatics/btt196. View

Mendoza M, Er E, Blenis J . The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011; 36(6):320-8. PMC: 3112285. DOI: 10.1016/j.tibs.2011.03.006. View

10.

Fribley A, Evenchik B, Zeng Q, Park B, Guan J, Zhang H . Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem. 2006; 281(42):31440-7. DOI: 10.1074/jbc.M604356200. View

11.

Davies B, Greenwood H, Dudley P, Crafter C, Yu D, Zhang J . Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012; 11(4):873-87. DOI: 10.1158/1535-7163.MCT-11-0824-T. View

12.

Garcia-Cao I, Duran A, Collado M, Carrascosa M, Martin-Caballero J, Flores J . Tumour-suppression activity of the proapoptotic regulator Par4. EMBO Rep. 2005; 6(6):577-83. PMC: 1369092. DOI: 10.1038/sj.embor.7400421. View

13.

Boghaert E, Sells S, Walid A, Malone P, Williams N, Weinstein M . Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues. Cell Growth Differ. 1997; 8(8):881-90. View

14.

Hodgkinson C, Sale G . Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment. Biochemistry. 2002; 41(2):561-9. DOI: 10.1021/bi010719z. View

15.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

16.

Wei Y, Jiang J, Liu D, Zhou J, Chen X, Zhang S . Cdc34-mediated degradation of ATF5 is blocked by cisplatin. J Biol Chem. 2008; 283(27):18773-81. DOI: 10.1074/jbc.M707879200. View

17.

Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K . MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010; 9(7):1956-67. DOI: 10.1158/1535-7163.MCT-09-1012. View

18.

Chaudhry P, Fabi F, Singh M, Parent S, Leblanc V, Asselin E . Prostate apoptosis response-4 mediates TGF-β-induced epithelial-to-mesenchymal transition. Cell Death Dis. 2014; 5:e1044. PMC: 3944278. DOI: 10.1038/cddis.2014.7. View

19.

Wang B, Kline C, Pastor D, Olson T, Frank B, Luu T . Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NF kappaB and microRNA network. Mol Cancer. 2010; 9:98. PMC: 2883962. DOI: 10.1186/1476-4598-9-98. View

20.

Basu A, Krishnamurthy S . Cellular responses to Cisplatin-induced DNA damage. J Nucleic Acids. 2010; 2010. PMC: 2929606. DOI: 10.4061/2010/201367. View