HDAC2 Attenuates TRAIL-induced Apoptosis of Pancreatic Cancer Cells

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2010 Apr 20

PMID 20398369

Citations 43

Authors

Susanne Schuler

Petra Fritsche

Sandra Diersch

Alexander Arlt

Roland M Schmid

Dieter Saur

Gunter Schneider

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions.

Results: Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Correspondingly, the more class I selective HDAC inhibitor (HDACI) valproic acid (VPA) synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5), accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells.

Conclusions: Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.

Citing Articles

Acquired Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Resistance of Human Colorectal Cancer Cells Is Linked to Histone Acetylation and Is Synergistically Ameliorated by Combination with HDAC Inhibitors.

Kim S, Shin M, Jin B, Seo S, Ha G, Kim S Dig Dis Sci. 2024; 69(9):3305-3317.

PMID: 39090444 DOI: 10.1007/s10620-024-08569-5.

Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs.

Elebo N, Abdel-Shafy E, Cacciatore S, Nweke E Front Genet. 2023; 14:1170571.

PMID: 37790705 PMC: 10544984. DOI: 10.3389/fgene.2023.1170571.

HDAC2 as a target for developing anti-cancer drugs.

Jo H, Shim K, Kim H, Jung H, Jeoung D Comput Struct Biotechnol J. 2023; 21:2048-2057.

PMID: 36968022 PMC: 10030825. DOI: 10.1016/j.csbj.2023.03.016.

Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer.

Xu Y, Zhu Q Int J Mol Sci. 2023; 24(5).

PMID: 36902253 PMC: 10003015. DOI: 10.3390/ijms24054820.

Histone Deacetylase Inhibitor Panobinostat Benefits the Therapeutic Efficacy of Oncolytic Herpes Simplex Virus Combined with PD-1/PD-L1 Blocking in Glioma and Squamous Cell Carcinoma Models.

Wu Y, Chen X, Wang L, Zhou X, Liu Y, Ji D Viruses. 2022; 14(12).

PMID: 36560800 PMC: 9781547. DOI: 10.3390/v14122796.

References

Retzer-Lidl M, Schmid R, Schneider G . Inhibition of CDK4 impairs proliferation of pancreatic cancer cells and sensitizes towards TRAIL-induced apoptosis via downregulation of survivin. Int J Cancer. 2007; 121(1):66-75. DOI: 10.1002/ijc.22619. View

Reichert M, Saur D, Hamacher R, Schmid R, Schneider G . Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 2007; 67(9):4149-56. DOI: 10.1158/0008-5472.CAN-06-4484. View

Schneider G, Henrich A, Greiner G, Wolf V, Lovas A, Wieczorek M . Cross talk between stimulated NF-kappaB and the tumor suppressor p53. Oncogene. 2010; 29(19):2795-806. DOI: 10.1038/onc.2010.46. View

Vogler M, Walczak H, Stadel D, Haas T, Genze F, Jovanovic M . Small molecule XIAP inhibitors enhance TRAIL-induced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma. Cancer Res. 2009; 69(6):2425-34. DOI: 10.1158/0008-5472.CAN-08-2436. View

Khanbolooki S, Nawrocki S, Arumugam T, Andtbacka R, Pino M, Kurzrock R . Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther. 2006; 5(9):2251-60. DOI: 10.1158/1535-7163.MCT-06-0075. View

Song J, An J, Kwon Y, Lee Y . Evidence for two modes of development of acquired tumor necrosis factor-related apoptosis-inducing ligand resistance. Involvement of Bcl-xL. J Biol Chem. 2006; 282(1):319-28. DOI: 10.1074/jbc.M608065200. View

Mitry E, Rachet B, Quinn M, Cooper N, Coleman M . Survival from cancer of the pancreas in England and Wales up to 2001. Br J Cancer. 2008; 99 Suppl 1:S21-3. PMC: 2557526. DOI: 10.1038/sj.bjc.6604576. View

Bicaku E, Marchion D, Schmitt M, Munster P . Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling. Cancer Res. 2008; 68(5):1513-9. DOI: 10.1158/0008-5472.CAN-07-2822. View

Fritsche P, Seidler B, Schuler S, Schnieke A, Gottlicher M, Schmid R . HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA. Gut. 2009; 58(10):1399-409. DOI: 10.1136/gut.2009.180711. View

10.

Bots M, Johnstone R . Rational combinations using HDAC inhibitors. Clin Cancer Res. 2009; 15(12):3970-7. DOI: 10.1158/1078-0432.CCR-08-2786. View

11.

Schneider G, Kramer O, Fritsche P, Schuler S, Schmid R, Saur D . Targeting histone deacetylases in pancreatic ductal adenocarcinoma. J Cell Mol Med. 2009; 14(6A):1255-63. PMC: 3828843. DOI: 10.1111/j.1582-4934.2009.00974.x. View

12.

Marks P, Xu W . Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem. 2009; 107(4):600-8. PMC: 2766855. DOI: 10.1002/jcb.22185. View

13.

Spange S, Wagner T, Heinzel T, Kramer O . Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2008; 41(1):185-98. DOI: 10.1016/j.biocel.2008.08.027. View

14.

Natoni F, Diolordi L, Santoni C, Gilardini Montani M . Sodium butyrate sensitises human pancreatic cancer cells to both the intrinsic and the extrinsic apoptotic pathways. Biochim Biophys Acta. 2005; 1745(3):318-29. DOI: 10.1016/j.bbamcr.2005.07.003. View

15.

Bai J, Sui J, Demirjian A, Vollmer Jr C, Marasco W, Callery M . Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Cancer Res. 2005; 65(6):2344-52. DOI: 10.1158/0008-5472.CAN-04-3502. View

16.

Trauzold A, WERMANN H, Arlt A, Schutze S, Schafer H, Oestern S . CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene. 2001; 20(31):4258-69. DOI: 10.1038/sj.onc.1204559. View

17.

Huang S, Okumura K, Sinicrope F . BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2009; 15(1):150-9. PMC: 2948485. DOI: 10.1158/1078-0432.CCR-08-1575. View

18.

Lehmann A, Denkert C, Budczies J, Buckendahl A, Darb-Esfahani S, Noske A . High class I HDAC activity and expression are associated with RelA/p65 activation in pancreatic cancer in vitro and in vivo. BMC Cancer. 2009; 9:395. PMC: 2779818. DOI: 10.1186/1471-2407-9-395. View

19.

Carew J, Giles F, Nawrocki S . Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008; 269(1):7-17. DOI: 10.1016/j.canlet.2008.03.037. View

20.

von Burstin J, Eser S, Paul M, Seidler B, Brandl M, Messer M . E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology. 2009; 137(1):361-71, 371.e1-5. DOI: 10.1053/j.gastro.2009.04.004. View