An IKKα-E2F1-BMI1 Cascade Activated by Infiltrating B Cells Controls Prostate Regeneration and Tumor Recurrence

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2013 Jun 26

PMID 23796898

Citations 43

Authors

Massimo Ammirante

Ali I Kuraishy

Shabnam Shalapour

Amy Strasner

Claudia Ramirez-Sanchez

Weizhou Zhang

Ahmed Shabaik

Michael Karin

Affiliations

Soon will be listed here.

Abstract

Androgen-deprived prostate cancer (PCa) is infiltrated by B lymphocytes that produce cytokines that activate IκB kinase α (IKKα) to accelerate the emergence of castration-resistant tumors. We now demonstrate that infiltrating B lymphocytes and IKKα are also required for androgen-dependent expansion of epithelial progenitors responsible for prostate regeneration. In these cells and in PCa cells, IKKα phosphorylates transcription factor E2F1 on a site that promotes its nuclear translocation, association with the coactivator CBP, and recruitment to critical genomic targets that include Bmi1, a key regulator of normal and cancerous prostate stem cell renewal. The IKKα-BMI1 pathway is also activated in human PCa.

Citing Articles

B cells and tertiary lymphoid structures in tumors: immunity cycle, clinical impact, and therapeutic applications.

Wu X, Huang Q, Chen X, Zhang B, Liang J, Zhang B Theranostics. 2025; 15(2):605-631.

PMID: 39744696 PMC: 11671382. DOI: 10.7150/thno.105423.

NF-κB signaling pathway in tumor microenvironment.

Cao Y, Yi Y, Han C, Shi B Front Immunol. 2024; 15:1476030.

PMID: 39493763 PMC: 11530992. DOI: 10.3389/fimmu.2024.1476030.

Unveiling the Molecular Landscape of Mutant Prostate Cancer: Insights and Prospects for Targeted Therapeutic Strategies.

Hwang K, Yun J, Kim H Int J Mol Sci. 2023; 24(21).

PMID: 37958805 PMC: 10650174. DOI: 10.3390/ijms242115823.

Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma.

Bao J, Betzler A, Hess J, Brunner C Front Immunol. 2023; 14:1233085.

PMID: 37868967 PMC: 10586314. DOI: 10.3389/fimmu.2023.1233085.

Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression.

Wang R, Song S, Qin J, Yoshimura K, Peng F, Chu Y Cancer Cell. 2023; 41(8):1407-1426.e9.

PMID: 37419119 PMC: 10528152. DOI: 10.1016/j.ccell.2023.06.005.

References

Gulley J, Figg W, Dahut W . Treatment options for androgen-independent prostate cancer. Clin Adv Hematol Oncol. 2005; 1(1):49-57. View

Hu Y, Baud V, Oga T, Kim K, Yoshida K, Karin M . IKKalpha controls formation of the epidermis independently of NF-kappaB. Nature. 2001; 410(6829):710-4. DOI: 10.1038/35070605. View

Lukacs R, Memarzadeh S, Wu H, Witte O . Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell. 2010; 7(6):682-93. PMC: 3019762. DOI: 10.1016/j.stem.2010.11.013. View

Dvorak H . Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986; 315(26):1650-9. DOI: 10.1056/NEJM198612253152606. View

Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin. 2012; 62(1):10-29. DOI: 10.3322/caac.20138. View

Ohtani K, DeGregori J, Nevins J . Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci U S A. 1995; 92(26):12146-50. PMC: 40313. DOI: 10.1073/pnas.92.26.12146. View

Rahemtulla A, Schilham M, Kundig T, Sambhara S, Narendran A, Arabian A . Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature. 1991; 353(6340):180-4. DOI: 10.1038/353180a0. View

Tu Z, Prajapati S, Park K, Kelly N, Yamamoto Y, Gaynor R . IKK alpha regulates estrogen-induced cell cycle progression by modulating E2F1 expression. J Biol Chem. 2006; 281(10):6699-706. DOI: 10.1074/jbc.M512439200. View

Hoberg J, Popko A, Ramsey C, Mayo M . IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol Cell Biol. 2005; 26(2):457-71. PMC: 1346914. DOI: 10.1128/MCB.26.2.457-471.2006. View

10.

Iyer N, Ozdag H, Caldas C . p300/CBP and cancer. Oncogene. 2004; 23(24):4225-31. DOI: 10.1038/sj.onc.1207118. View

11.

Ben-Neriah Y, Karin M . Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol. 2011; 12(8):715-23. DOI: 10.1038/ni.2060. View

12.

Chen J, Trounstine M, Alt F, Young F, Kurahara C, Loring J . Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int Immunol. 1993; 5(6):647-56. DOI: 10.1093/intimm/5.6.647. View

13.

Yamamoto Y, Verma U, Prajapati S, Kwak Y, Gaynor R . Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 2003; 423(6940):655-9. DOI: 10.1038/nature01576. View

14.

Trouche D, Kouzarides T . E2F1 and E1A(12S) have a homologous activation domain regulated by RB and CBP. Proc Natl Acad Sci U S A. 1996; 93(4):1439-42. PMC: 39957. DOI: 10.1073/pnas.93.4.1439. View

15.

Ammirante M, Luo J, Grivennikov S, Nedospasov S, Karin M . B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010; 464(7286):302-5. PMC: 2866639. DOI: 10.1038/nature08782. View

16.

Jacobs J, Scheijen B, Voncken J, Kieboom K, Berns A, van Lohuizen M . Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999; 13(20):2678-90. PMC: 317101. DOI: 10.1101/gad.13.20.2678. View

17.

Ianari A, Gallo R, Palma M, Alesse E, Gulino A . Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage. J Biol Chem. 2004; 279(29):30830-5. DOI: 10.1074/jbc.M402403200. View

18.

Karin M . NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 2010; 1(5):a000141. PMC: 2773649. DOI: 10.1101/cshperspect.a000141. View

19.

Karhadkar S, Bova G, Abdallah N, Dhara S, Gardner D, Maitra A . Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004; 431(7009):707-12. DOI: 10.1038/nature02962. View

20.

Velnar T, Bailey T, Smrkolj V . The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res. 2009; 37(5):1528-42. DOI: 10.1177/147323000903700531. View