BCL2 and CASP8 Regulation by NF-kappaB Differentially Affect Mitochondrial Function and Cell Fate in Antiestrogen-sensitive and -resistant Breast Cancer Cells

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2010 Feb 16

PMID 20154269

Citations 51

Authors

Ruchi Nehra

Rebecca B Riggins

Ayesha N Shajahan

Alan Zwart

Anatasha C Crawford

Robert Clarke

Affiliations

Soon will be listed here.

Abstract

Resistance to endocrine therapies remains a major problem in the management of estrogen receptor-alpha (ER)-positive breast cancer. We show that inhibition of NF-kappaB (p65/RELA), either by overexpression of a mutant IkappaB (IkappaBSR) or a small-molecule inhibitor of NF-kappaB (parthenolide; IC(50)=500 nM in tamoxifen-resistant cells), synergistically restores sensitivity to 4-hydroxytamoxifen (4HT) in resistant MCF7/RR and MCF7/LCC9 cells and further sensitizes MCF-7 and MCF7/LCC1 control cells to 4HT. These effects are independent of changes in either cell cycle distribution or in the level of autophagy measured by inhibition of p62/SQSTM1 expression and cleavage of LC3. NF-kappaB inhibition restores the ability of 4HT to decrease BCL2 expression, increase mitochondrial membrane permeability, and induce a caspase-dependent apoptotic cell death in resistant cells. Each of these effects is reversed by a caspase 8 (CASP8)-specific inhibitor that blocks enzyme-substrate binding. Thus, increased activation of NF-kappaB can alter sensitivity to tamoxifen by modulating CASP8 activity, with consequent effects on BCL2 expression, mitochondrial function, and apoptosis. These data provide significant new insights into how molecular signaling affects antiestrogen responsiveness and strongly suggest that a combination of parthenolide and tamoxifen may offer a novel therapeutic approach to the management of some ER-positive breast cancers.

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References

Drew P, Franzoso G, Becker K, Bours V, Carlson L, Siebenlist U . NF kappa B and interferon regulatory factor 1 physically interact and synergistically induce major histocompatibility class I gene expression. J Interferon Cytokine Res. 1995; 15(12):1037-45. DOI: 10.1089/jir.1995.15.1037. View

Basanez G, Nechushtan A, Drozhinin O, Chanturiya A, Choe E, Tutt S . Bax, but not Bcl-xL, decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. Proc Natl Acad Sci U S A. 1999; 96(10):5492-7. PMC: 21887. DOI: 10.1073/pnas.96.10.5492. View

Crawford A, Riggins R, Shajahan A, Zwart A, Clarke R . Co-inhibition of BCL-W and BCL2 restores antiestrogen sensitivity through BECN1 and promotes an autophagy-associated necrosis. PLoS One. 2010; 5(1):e8604. PMC: 2797635. DOI: 10.1371/journal.pone.0008604. View

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T . Cancer statistics, 2008. CA Cancer J Clin. 2008; 58(2):71-96. DOI: 10.3322/CA.2007.0010. View

Riggins R, Bouton A, Liu M, Clarke R . Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. Vitam Horm. 2005; 71:201-37. DOI: 10.1016/S0083-6729(05)71007-4. View

Vindelov L, Christensen I, Nissen N . A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry. 1983; 3(5):323-7. DOI: 10.1002/cyto.990030503. View

Narita M, Shimizu S, Ito T, Chittenden T, Lutz R, Matsuda H . Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S A. 1998; 95(25):14681-6. PMC: 24509. DOI: 10.1073/pnas.95.25.14681. View

Clarke R, Liu M, Bouker K, Gu Z, Lee R, Zhu Y . Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene. 2003; 22(47):7316-39. DOI: 10.1038/sj.onc.1206937. View

Bouker K, Skaar T, Fernandez D, OBrien K, Riggins R, Cao D . interferon regulatory factor-1 mediates the proapoptotic but not cell cycle arrest effects of the steroidal antiestrogen ICI 182,780 (faslodex, fulvestrant). Cancer Res. 2004; 64(11):4030-9. DOI: 10.1158/0008-5472.CAN-03-3602. View

10.

Kuske B, Naughton C, Moore K, Macleod K, Miller W, Clarke R . Endocrine therapy resistance can be associated with high estrogen receptor alpha (ERalpha) expression and reduced ERalpha phosphorylation in breast cancer models. Endocr Relat Cancer. 2006; 13(4):1121-33. DOI: 10.1677/erc.1.01257. View

11.

Nakshatri H, Rice S, Bhat-Nakshatri P . Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene. 2004; 23(44):7330-44. DOI: 10.1038/sj.onc.1207995. View

12.

Lilling G, Hacohen H, Nordenberg J, Livnat T, Rotter V, Sidi Y . Differential sensitivity of MCF-7 and LCC2 cells, to multiple growth inhibitory agents: possible relation to high bcl-2/bax ratio?. Cancer Lett. 2000; 161(1):27-34. DOI: 10.1016/s0304-3835(00)00579-6. View

13.

Riggins R, Zwart A, Nehra R, Clarke R . The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol Cancer Ther. 2005; 4(1):33-41. View

14.

Komatsu M, Waguri S, Koike M, Sou Y, Ueno T, Hara T . Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007; 131(6):1149-63. DOI: 10.1016/j.cell.2007.10.035. View

15.

Clarke R, Shajahan A, Riggins R, Cho Y, Crawford A, Xuan J . Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells. J Steroid Biochem Mol Biol. 2009; 114(1-2):8-20. PMC: 2768542. DOI: 10.1016/j.jsbmb.2008.12.023. View

16.

Romanelli S, Perego P, Pratesi G, Carenini N, Tortoreto M, Zunino F . In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol. 1998; 41(5):385-90. DOI: 10.1007/s002800050755. View

17.

Eskes R, Desagher S, Antonsson B, Martinou J . Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol. 2000; 20(3):929-35. PMC: 85210. DOI: 10.1128/MCB.20.3.929-935.2000. View

18.

Clarke R, Leonessa F, Welch J, Skaar T . Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev. 2001; 53(1):25-71. View

19.

Wen J, You K, Lee S, Song C, Kim D . Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem. 2002; 277(41):38954-64. DOI: 10.1074/jbc.M203842200. View

20.

Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 1998; 94(4):481-90. DOI: 10.1016/s0092-8674(00)81589-5. View