PARP1 Bound to XRCC2 Promotes Tumor Progression in Colorectal Cancer

Overview

Journal Discov Oncol

Publisher Springer

Specialty Oncology

Date 2024 Jun 21

PMID 38907095

Authors

Kaiwu Xu

Zhige Yu

Tailiang Lu

Wei Peng

Yongqiang Gong

Chaowu Chen

Affiliations

Soon will be listed here.

Abstract

Background: By complexing poly (ADP-ribose) (PAR) in reaction to broke strand, PAR polymerase1 (PARP1) acts as the key enzyme participated in DNA repair. However, recent studies suggest that unrepaired DNA breaks results in persistent PARP1 activation, which leads to a progressively reduce in hexokinase1 (HK1) activity and cell death. PARP-1 is TCF-4/β-A novel co activator of gene transactivation induced by catenin may play a role in the development of colorectal cancer. The molecular mechanism of PARP1 remains elusive.

Methods: 212 colorectal cancer (CRC) patients who had the operation at our hospital were recruited. PARP1 expression was evaluated by immunohistochemistry. Stable CRC cell lines with low or high PARP1 expression were constructed. Survival analysis was computed based on PARP1 expression. The cell proliferation was tested by CCK-8 and Colony formation assay. The interaction of PARP1 and XRCC2 was detected by immunoprecipitation (IP) analysis.

Results: Compared with matching adjacent noncancerous tissue, PARP1 was upregulated in CRC tissue which was correlated with the degree of differentiation, TNM stage, depth of invasion, metastasis, and survival. In addition, after constructing CRC stable cell lines with abnormal expression of PARP1, we found that overexpression of PARP1 promoted proliferation, and demonstrated the interaction between PARP1 and XRCC2 in CRC cells through immunoprecipitation (IP) analysis. Moreover, the inhibitor of XRCC2 can suppress the in vitro proliferation arousing by upregulation of PARP1.

Conclusions: PARP1 was upregulated in CRC cells and promoted cell proliferation. Furthermore, the expression status of PARP1 was significantly correlated with some clinicopathological features and 5-year survival.

Citing Articles

Recombinant Lectin Exerts Differential Proapoptotic Activity on EGFR and EGFR Colon Cancer Cells and Provokes T Cell-Assisted Antitumor Responses in Mice.

Lujan-Mendez F, Garcia-Lopez P, Berumen L, Garcia-Alcocer G, Ferriz-Martinez R, Ramirez-Carrera A Pharmaceuticals (Basel). 2025; 18(2).

PMID: 40006027 PMC: 11858825. DOI: 10.3390/ph18020213.

Leveraging PARP-1/2 to Target Distant Metastasis.

Frederick M, Abdesselam D, Clouvel A, Croteau L, Hassan S Int J Mol Sci. 2024; 25(16).

PMID: 39201718 PMC: 11354653. DOI: 10.3390/ijms25169032.

References

Dedes K, Wilkerson P, Wetterskog D, Weigelt B, Ashworth A, Reis-Filho J . Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle. 2011; 10(8):1192-9. PMC: 3117132. DOI: 10.4161/cc.10.8.15273. View

Schaaf L, Schwab M, Ulmer C, Heine S, Murdter T, Schmid J . Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest. Cancer Res. 2016; 76(10):2868-75. DOI: 10.1158/0008-5472.CAN-15-2908. View

Rank L, Veith S, Gwosch E, Demgenski J, Ganz M, Jongmans M . Analyzing structure-function relationships of artificial and cancer-associated PARP1 variants by reconstituting TALEN-generated HeLa PARP1 knock-out cells. Nucleic Acids Res. 2016; 44(21):10386-10405. PMC: 5137445. DOI: 10.1093/nar/gkw859. View

Li J, Zhang N, Song L, Liao W, Jiang L, Gong L . Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res. 2008; 14(11):3319-26. DOI: 10.1158/1078-0432.CCR-07-4054. View

Pieper A, Walles T, Wei G, Clements E, Verma A, Snyder S . Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption. Mol Med. 2000; 6(4):271-82. PMC: 1949947. View

Jain P, Patel B . Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update. Eur J Med Chem. 2019; 165:198-215. DOI: 10.1016/j.ejmech.2019.01.024. View

Bryant H, Schultz N, Thomas H, Parker K, Flower D, Lopez E . Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005; 434(7035):913-7. DOI: 10.1038/nature03443. View

Arnold M, Sierra M, Laversanne M, Soerjomataram I, Jemal A, Bray F . Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2016; 66(4):683-691. DOI: 10.1136/gutjnl-2015-310912. View

Hoeijmakers J . DNA damage, aging, and cancer. N Engl J Med. 2009; 361(15):1475-85. DOI: 10.1056/NEJMra0804615. View

10.

Masutani M, Suzuki H, Kamada N, Watanabe M, Ueda O, Nozaki T . Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. Proc Natl Acad Sci U S A. 1999; 96(5):2301-4. PMC: 26778. DOI: 10.1073/pnas.96.5.2301. View

11.

Li Y, Li S, Wu Z, Hu F, Zhu L, Zhao X . Polymorphisms in genes of APE1, PARP1, and XRCC1: risk and prognosis of colorectal cancer in a northeast Chinese population. Med Oncol. 2013; 30(2):505. DOI: 10.1007/s12032-013-0505-z. View

12.

Eliasson M, Sampei K, Mandir A, Hurn P, Traystman R, Bao J . Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997; 3(10):1089-95. DOI: 10.1038/nm1097-1089. View

13.

Santos J, Funck A, Silva-Fernandes I, Rabenhorst S, Martinez C, Ribeiro M . Effect of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in patients with colorectal cancer. Int J Mol Sci. 2014; 15(10):17333-43. PMC: 4227165. DOI: 10.3390/ijms151017333. View

14.

Fouquerel E, Goellner E, Yu Z, Gagne J, Barbi de Moura M, Feinstein T . ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion. Cell Rep. 2014; 8(6):1819-1831. PMC: 4177344. DOI: 10.1016/j.celrep.2014.08.036. View

15.

McAndrew E, Lepage C, McManus K . The synthetic lethal killing of RAD54B-deficient colorectal cancer cells by PARP1 inhibition is enhanced with SOD1 inhibition. Oncotarget. 2016; 7(52):87417-87430. PMC: 5349998. DOI: 10.18632/oncotarget.13654. View

16.

Xu K, Song X, Chen Z, Qin C, He Y, Zhan W . XRCC2 promotes colorectal cancer cell growth, regulates cell cycle progression, and apoptosis. Medicine (Baltimore). 2014; 93(28):e294. PMC: 4603138. DOI: 10.1097/MD.0000000000000294. View

17.

Nosho K, Yamamoto H, Mikami M, Taniguchi H, Takahashi T, Adachi Y . Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis. Eur J Cancer. 2006; 42(14):2374-81. DOI: 10.1016/j.ejca.2006.01.061. View

18.

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View

19.

Xu K, Song X, Chen Z, Qin C, He Y . XRCC2 rs3218536 polymorphism decreases the sensitivity of colorectal cancer cells to poly(ADP-ribose) polymerase 1 inhibitor. Oncol Lett. 2014; 8(3):1222-1228. PMC: 4114618. DOI: 10.3892/ol.2014.2236. View

20.

Burns N, Gold B . The effect of 3-methyladenine DNA glycosylase-mediated DNA repair on the induction of toxicity and diabetes by the beta-cell toxicant streptozotocin. Toxicol Sci. 2006; 95(2):391-400. DOI: 10.1093/toxsci/kfl164. View