Inhibition of IL-6 expression in LNCaP prostate cancer cells by a combination of atorvastatin and celecoxib

Wang,Huaqian; Cui,Xiao-Xing; Goodin,Susan; Ding,Ning; Van Doren,Jeremiah; Du,Zhiyun; Huang,Mou-Tuan; Liu,Yue; Cheng,Xiaodong; Dipaola,Robert S.; Conney,Allan  H.; Zheng,Xi

doi:10.3892/or.2013.2885

Inhibition of IL-6 expression in LNCaP prostate cancer cells by a combination of atorvastatin and celecoxib

Authors:
- Huaqian Wang
- Xiao-Xing Cui
- Susan Goodin
- Ning Ding
- Jeremiah Van Doren
- Zhiyun Du
- Mou-Tuan Huang
- Yue Liu
- Xiaodong Cheng
- Robert S. Dipaola
- Allan H. Conney
- Xi Zheng
View Affiliations

Affiliations: Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou 510006, P.R. China, Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA, The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA, School of Life Sciences and Technology, East Hospital, Tongji University, Shanghai 200092, P.R. China
Published online on: November 29, 2013 https://doi.org/10.3892/or.2013.2885
Pages: 835-841

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 present study, we investigated the effect of a combination of atorvastatin and celecoxib on the formation of interleukin (IL)-6, a cytokine that is increased during the progression of LNCaP tumors from androgen dependence to androgen independence. Culturing LNCaP cells in androgen‑depleted (AD) medium increased the levels of IL-6 and survivin, and treatment of the cells in AD medium with a combination of atorvastatin and celecoxib strongly inhibited the increase in IL-6 and survivin which is one of the downstream targets of the IL-6 signaling pathway. Addition of recombinant IL-6 partially abrogated the combined effect of atorvastatin and celecoxib on apoptosis in LNCaP cells cultured in AD medium. In SCID mice, we found that the levels of IL-6 and survivin expression were increased when LNCaP tumors became androgen-independent. Treatment of the mice with atorvastatin or celecoxib alone caused decrease in the levels of IL-6 and survivin as LNCaP tumors became androgen-independent, but treatment of the mice with a combination of celecoxib and atorvastatin resulted in a much stronger inhibition in the increase in IL-6 and survivin expression. Our results indicate that decreases in IL-6 and survivin levels by atorvastatin and celecoxib administration are associated with increased apoptosis in LNCaP cells treated with this drug combination. Our in vivo studies indicate that the inhibitory effect of a combination of atorvastatin and celecoxib on the progression of androgen-dependent LNCaP xenograft tumors to androgen independence is associated with inhibition of the increase in IL-6 and survivin that occurs when androgen-dependent LNCaP prostate tumors become androgen-independent.

View Figures

View References

1	Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin M, Vogelzang NJ, Wade JL III, Bennett CL and Scher HI; American Society of Clinical Oncology. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 25:1596–1605. 2007. View Article : Google Scholar
2	Devlin HL and Mudryj M: Progression of prostate cancer: multiple pathways to androgen independence. Cancer Lett. 274:177–186. 2009. View Article : Google Scholar : PubMed/NCBI
3	So A, Gleave M, Hurtado-Col A and Nelson C: Mechanisms of the development of androgen independence in prostate cancer. World J Urol. 23:1–9. 2005. View Article : Google Scholar : PubMed/NCBI
4	Schröder FH: Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. Eur Urol. 53:1129–1137. 2008.
5	Chi KN, Bjartell A, Dearnaley D, Saad F, Schröder FH, Sternberg C, Tombal B and Visakorpi T: Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur Urol. 56:594–605. 2009. View Article : Google Scholar : PubMed/NCBI
6	Pilat MJ, Kamradt JM and Pienta KJ: Hormone resistance in prostate cancer. Cancer Metastasis Rev. 17:373–381. 1999. View Article : Google Scholar
7	Stein MN, Goodin S and Dipaola RS: Abiraterone in prostate cancer: a new angle to an old problem. Clin Cancer Res. 18:1848–1854. 2012. View Article : Google Scholar : PubMed/NCBI
8	Seruga B and Tannock IF: Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol. 29:3686–3694. 2011. View Article : Google Scholar : PubMed/NCBI
9	Farnier M and Davignon J: Current and future treatment of hyperlipidemia: the role of statins. Am J Cardiol. 82:3J–10J. 1998. View Article : Google Scholar : PubMed/NCBI
10	Malhotra HS and Goa KL: Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia. Drugs. 61:1835–1881. 2001. View Article : Google Scholar : PubMed/NCBI
11	Jacobs EJ, Rodriguez C, Bain EB, Wang Y, Thun MJ and Calle EE: Cholesterol-lowering drugs and advanced prostate cancer incidence in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev. 16:2213–2217. 2007. View Article : Google Scholar : PubMed/NCBI
12	Flick ED, Habel LA, Chan KA, et al: Statin use and risk of prostate cancer in the California Men’s Health Study cohort. Cancer Epidemiol Biomarkers Prev. 16:2218–2225. 2007.
13	Hamilton RJ, Banez LL, Aronson WJ, Terris MK, Platz EA, Kane CJ, Presti JC Jr, Amling CL and Freedland SJ: Statin medication use and the risk of biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Cancer. 116:3389–3398. 2010. View Article : Google Scholar
14	Abedinpour P, Baron VT, Welsh J and Borgström P: Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo. Prostate. 71:813–823. 2011. View Article : Google Scholar : PubMed/NCBI
15	Dandekar DS, Lopez M, Carey RI and Lokeshwar BL: Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells. Int J Cancer. 115:484–492. 2005. View Article : Google Scholar : PubMed/NCBI
16	Harris RE: Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology. 17:55–67. 2009. View Article : Google Scholar : PubMed/NCBI
17	Reddy BS, Wang CX, Kong AN, Khor TO, Zheng X, Steele VE, Kopelovich L and Rao CV: Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. Cancer Res. 66:4542–4546. 2006. View Article : Google Scholar : PubMed/NCBI
18	Zheng X, Cui XX, Gao Z, Zhao Y, Lin Y, Shih WJ, Huang MT, Liu Y, Rabson A, Reddy B, Yang CS and Conney AH: Atorvastatin and celecoxib in combination inhibits the progression of androgen-dependent LNCaP xenograft prostate tumors to androgen independence. Cancer Prev Res. 3:114–124. 2010. View Article : Google Scholar : PubMed/NCBI
19	Zheng X, Cui XX, Avila GE, Huang MT, Liu Y, Patel J, Kong AN, Paulino R, Shih WJ, Lin Y, Rabson AB, Reddy BS and Conney AH: Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clin Cancer Res. 13:5480–5487. 2007. View Article : Google Scholar : PubMed/NCBI
20	Hammacher A, Thompson EW and Williams ED: Interleukin-6 is a potent inducer of S100P, which is up-regulated in androgen-refractory and metastatic prostate cancer. Int J Biochem Cell Biol. 37:442–450. 2005. View Article : Google Scholar : PubMed/NCBI
21	Chen T, Wang LH and Farrar WL: Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer Res. 60:2132–2135. 2000.
22	Kim O, Jiang T, Xie Y, Guo Z, Chen H and Qiu Y: Synergism of cytoplasmic kinases in IL6-induced ligand-independent activation of androgen receptor in prostate cancer cells. Oncogene. 23:1838–1844. 2004. View Article : Google Scholar : PubMed/NCBI
23	Gazi MH, Gong A, Donkena KV and Young CY: Sodium selenite inhibits interleukin-6-mediated androgen receptor activation in prostate cancer cells via upregulation of c-Jun. Clin Chim Acta. 380:145–150. 2007. View Article : Google Scholar : PubMed/NCBI
24	Smith PC, Hobisch A, Lin DL, Culig Z and Keller ET: Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev. 12:33–40. 2001. View Article : Google Scholar : PubMed/NCBI
25	Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, Moser PL, Fuchs D, Hobisch A and Culig Z: Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer. 16:155–169. 2009. View Article : Google Scholar : PubMed/NCBI
26	Lee SO, Lou W, Johnson CS, Trump DL and Gao AC: Interleukin-6 protects LNCaP cells from apoptosis induced by androgen deprivation through the Stat3 pathway. Prostate. 60:178–186. 2004. View Article : Google Scholar : PubMed/NCBI
27	Wei X, Du ZY, Cui XX, Verano M, Mo RQ, Tang ZK, Conney AH, Zheng X and Zhang K: Effects of cyclohexanone analogues of curcumin on growth, apoptosis and NF-κB activity in PC-3 human prostate cancer cells. Oncol Lett. 4:279–284. 2012.
28	Zheng X, Chang RL, Cui XX, Avila GE, Hebbar V, Garzotto M, Shih WJ, Lin Y, Lu SE, Rabson AB, Kong AN and Conney AH: Effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate Cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. Clin Cancer Res. 12:3444–3451. 2006.
29	Zheng X, Cui XX, Huang MT, Liu Y, Wagner GC, Lin Y, Shih WJ, Lee MJ, Yang CS and Conney AH: Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise. Nutr Cancer. 64:1029–1037. 2012. View Article : Google Scholar : PubMed/NCBI
30	Hsu JC: Comparisons: Theory and Methods. Chapman and Hall; New York, NY: 1996, View Article : Google Scholar
31	Zhao L, Wientjes MG and Au JL: Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res. 10:7994–8004. 2004. View Article : Google Scholar : PubMed/NCBI
32	Hirano T: The biology of interleukin-6. Chem Immunol. 51:153–180. 1992. View Article : Google Scholar
33	Michalaki V, Syrigos K, Charles P and Waxman J: Serum levels of IL-6 and TNF-α correlate with clinicopathological features and patient survival in patients with prostate cancer. Br J Cancer. 90:2312–2316. 2004.
34	Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T, Asakura H and Murai M: Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res. 6:2702–2706. 2000.PubMed/NCBI
35	Altieri DC: Targeting survivin in cancer. Cancer Lett. 332:225–228. 2013. View Article : Google Scholar : PubMed/NCBI
36	Shariat SF, Lotan Y, Saboorian H, Khoddami SM, Roehrborn CG, Slawin KM and Ashfaq R: Survivin expression is associated with features of biologically aggressive prostate carcinoma. Cancer. 100:751–757. 2004. View Article : Google Scholar : PubMed/NCBI
37	Costantino L and Barlocco D: STAT 3 as a target for cancer drug discovery. Curr Med Chem. 15:834–843. 2008. View Article : Google Scholar : PubMed/NCBI