Suppression of casein kinase 2 sensitizes tumor cells to antitumor TRAIL therapy by regulating the phosphorylation and localization of p65 in prostate cancer

Gang,Xiaokun; Wang,Yao; Wang,Yingdi; Zhao,Yu; Ding,Liya; Zhao,Jingwen; Sun,Lin; Wang,Guixia

doi:10.3892/or.2015.4123

Suppression of casein kinase 2 sensitizes tumor cells to antitumor TRAIL therapy by regulating the phosphorylation and localization of p65 in prostate cancer

Authors:
- Xiaokun Gang
- Yao Wang
- Yingdi Wang
- Yu Zhao
- Liya Ding
- Jingwen Zhao
- Lin Sun
- Guixia Wang
View Affiliations

Affiliations: Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin 130042, P.R. China, Department of Urology, Jilin Oncological Hospital, Changchun, Jilin 130021, P.R. China, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Published online on: July 13, 2015 https://doi.org/10.3892/or.2015.4123
Pages: 1599-1604

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in males. For PCa at the late hormone-refractory stage, substantial improvement in treatment strategies is critically needed. TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, but both intrinsic and acquired resistance to TRAIL poses a huge problem in establishing clinically effective TRAIL therapies. In the present study, we examined the role played by casein kinase 2 (CK2) in the TRAIL‑induced nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) pathway in a PCa cell line. Downregulation of CK2 combined with a sub-dose of TRAIL suppressed p65 phosphorylation at serine 536. The combination treatment of TRAIL and the CK2 inhibitor decreased p65 nuclear translocation. Under the treatment of a sub-dose of TRAIL, downregulation of CK2, using both genetic and pharmacological approaches, decreased the transcriptional activity of NF-κB and the expression of NF-κB downstream anti-apoptosis genes. Therefore, we provided novel molecular mechanistic insight reporting that CK2 regulates the sensitivity of PCa cells to the antitumor effect of TRAIL. This is important for understanding how the TRAIL pathway is disrupted in PCa and may help to develop an effective combinatorial therapy for PCa.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Allen JE and El-Deiry WS: Regulation of the human TRAIL gene. Cancer Biol Ther. 13:1143–1151. 2012. View Article : Google Scholar : PubMed/NCBI
3	Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, et al: Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 104:155–162. 1999. View Article : Google Scholar : PubMed/NCBI
4	Morales JC, Ruiz-Magaña MJ and Ruiz-Ruiz C: Regulation of the resistance to TRAIL-induced apoptosis in human primary T lymphocytes: Role of NF-kappaB inhibition. Mol Immunol. 44:2587–2597. 2007. View Article : Google Scholar : PubMed/NCBI
5	Kim YS, Schwabe RF, Qian T, Lemasters JJ and Brenner DA: TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells. Hepatology. 36:1498–1508. 2002.PubMed/NCBI
6	Keane MM, Rubinstein Y, Cuello M, Ettenberg SA, Banerjee P, Nau MM and Lipkowitz S: Inhibition of NF-kappaB activity enhances TRAIL mediated apoptosis in breast cancer cell lines. Breast Cancer Res Treat. 64:211–219. 2000. View Article : Google Scholar
7	Jani TS, DeVecchio J, Mazumdar T, Agyeman A and Houghton JA: Inhibition of NF-kappaB signaling by quinacrine is cytotoxic to human colon carcinoma cell lines and is synergistic in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or oxaliplatin. J Biol Chem. 285:19162–19172. 2010. View Article : Google Scholar : PubMed/NCBI
8	Ozören N and El-Deiry WS: Defining characteristics of types I and II apoptotic cells in response to TRAIL. Neoplasia. 4:551–557. 2002. View Article : Google Scholar : PubMed/NCBI
9	Stuckey DW and Shah K: TRAIL on trial: Preclinical advances in cancer therapy. Trends Mol Med. 19:685–694. 2013. View Article : Google Scholar : PubMed/NCBI
10	Gonzalvez F and Ashkenazi A: New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene. 29:4752–4765. 2010. View Article : Google Scholar : PubMed/NCBI
11	Voelkel-Johnson C: TRAIL-mediated signaling in prostate, bladder and renal cancer. Nat Rev Urol. 8:417–427. 2011. View Article : Google Scholar : PubMed/NCBI
12	Chen C, Edelstein LC and Gélinas C: The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol. 20:2687–2695. 2000. View Article : Google Scholar : PubMed/NCBI
13	Luo W, Yu WD, Ma Y, Chernov M, Trump DL and Johnson CS: Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D(3) antitumor activity in human prostate cancer cells. Cancer Res. 73:2289–2297. 2013. View Article : Google Scholar : PubMed/NCBI
14	Agarwal M, Nitta RT and Li G: Casein kinase 2: A novel player in glioblastoma therapy and cancer stem cells. J Mol Genet Med. 8:82013.
15	Wang G, Ahmad KA and Ahmed K: Role of protein kinase CK2 in the regulation of tumor necrosis factor-related apoptosis inducing ligand-induced apoptosis in prostate cancer cells. Cancer Res. 66:2242–2249. 2006. View Article : Google Scholar : PubMed/NCBI
16	Orzechowska E, Kozłowska E, Staroń K and Trzcińska-Danielewicz J: Time schedule-dependent effect of the CK2 inhibitor TBB on PC-3 human prostate cancer cell viability. Oncol Rep. 27:281–285. 2012.
17	Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, Bagchi A, Simon JA and Huang H: Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 12:1108–1114. 2010. View Article : Google Scholar : PubMed/NCBI
18	Silva L, Oh HS, Chang L, Yan Z, Triezenberg SJ and Knipe DM: Roles of the nuclear lamina in stable nuclear association and assembly of a herpesviral transactivator complex on viral immediate-early genes. MBio. 3:e00300–e00311. 2012. View Article : Google Scholar : PubMed/NCBI
19	Liu J, Ma J, Wu Z, Li W, Zhang D, Han L, Wang F, Reindl KM, Wu E and Ma Q: Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling. BMC Cancer. 14:6862014. View Article : Google Scholar
20	Hu J, Nakano H, Sakurai H and Colburn NH: Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-kappaB activation and transformation in resistant JB6 cells. Carcinogenesis. 25:1991–2003. 2004. View Article : Google Scholar : PubMed/NCBI
21	Harikumar KB, Kunnumakkara AB, Ahn KS, Anand P, Krishnan S, Guha S and Aggarwal BB: Modification of the cysteine residues in IkappaBalpha kinase and NF-kappaB (p65) by xanthohumol leads to suppression of NF-kappaB-regulated gene products and potentiation of apoptosis in leukemia cells. Blood. 113:2003–2013. 2009. View Article : Google Scholar
22	Kim HR, Kim K, Lee KH, Kim SJ and Kim J: Inhibition of casein kinase 2 enhances the death ligand- and natural killer cell-induced hepatocellular carcinoma cell death. Clin Exp Immunol. 152:336–344. 2008. View Article : Google Scholar : PubMed/NCBI
23	Llobet D, Eritja N, Encinas M, Llecha N, Yeramian A, Pallares J, Sorolla A, Gonzalez-Tallada FJ, Matias-Guiu X and Dolcet X: CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells. Oncogene. 27:2513–2524. 2008. View Article : Google Scholar
24	Hundsdörfer C, Hemmerling HJ, Hamberger J, Le Borgne M, Bednarski P, Götz C, Totzke F and Jose J: Novel indeno[1,2-b] indoloquinones as inhibitors of the human protein kinase CK2 with antiproliferative activity towards a broad panel of cancer cell lines. Biochem Biophys Res Commun. 424:71–75. 2012. View Article : Google Scholar
25	Wang G, Ahmad KA, Unger G, Slaton JW and Ahmed K: CK2 signaling in androgen-dependent and -independent prostate cancer. J Cell Biochem. 99:382–391. 2006. View Article : Google Scholar : PubMed/NCBI
26	Tong L, Yuan Y and Wu S: Therapeutic microRNAs targeting the NF-kappa B signaling circuits of cancers. Adv Drug Deliv Rev. 81:1–15. 2015. View Article : Google Scholar
27	Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, Hayward SW and Matusik RJ: Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression. Oncogene. Sep 15–2014.(Epub ahead of print).http://dx.doi.org/10.1038/onc.2014.302.
28	Eddy SF, Guo S, Demicco EG, Romieu-Mourez R, Landesman-Bollag E, Seldin DC and Sonenshein GE: Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res. 65:11375–11383. 2005. View Article : Google Scholar : PubMed/NCBI
29	Manni S, Brancalion A, Mandato E, Tubi LQ, Colpo A, Pizzi M, Cappellesso R, Zaffino F, Di Maggio SA, Cabrelle A, et al: Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells. PLoS One. 8:e752802013. View Article : Google Scholar
30	Kim KJ, Cho KD, Jang KY, Kim HA, Kim HK, Lee HK and Im SY: Platelet-activating factor enhances tumour metastasis via the reactive oxygen species-dependent protein kinase casein kinase 2-mediated nuclear factor-κB activation. Immunology. 143:21–32. 2014. View Article : Google Scholar : PubMed/NCBI
31	Douillette A, Bibeau-Poirier A, Gravel SP, Clément JF, Chénard V, Moreau P and Servant MJ: The proinflammatory actions of angiotensin II are dependent on p65 phosphorylation by the IkappaB kinase complex. J Biol Chem. 281:13275–13284. 2006. View Article : Google Scholar : PubMed/NCBI
32	Gutierrez H, O'Keeffe GW, Gavaldà N, Gallagher D and Davies AM: Nuclear factor kappa B signaling either stimulates or inhibits neurite growth depending on the phosphorylation status of p65/RelA. J Neurosci. 28:8246–8256. 2008. View Article : Google Scholar : PubMed/NCBI