Interleukin 6, a Nuclear Factor-κB Target, Predicts Resistance to Docetaxel in Hormone-Independent Prostate Cancer and Nuclear Factor-κB Inhibition by PS-1145 Enhances Docetaxel Antitumor Activity

Abstract

Purpose: To investigate whether nuclear factor nB (NF-nB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-nB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-nB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients. Experimental Design: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-nB inhibitor PS-1145 (an inhibitor of InB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-nB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxelbased chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter. Results: PC-3 and DU-145 cells had higher NF-nB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-nB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-nB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8 F 9.5 pg/mL in PSA responders versus 36.7 F 20.8 pg/mL (P = 0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P = 0.0007). On multivariate analysis, pretreatment IL-6 (P = 0.05) was an independent prognostic factor for time to disease progression and survival. Conclusions: Inhibition of NF-nB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…The comparison of pre-and posttreatment samples showed increased expression of cytokines regulated by the NF-kB pathway. These data are in concordance with our results showing an increased expression in treated tumors of NF-kB subunits and NF-kB-regulated cytokines, such as IL-6, adding support to a body of evidence on the involvement of this pathway in resistance to chemotherapy in prostate cancer (11). On the other hand, NF-kB activation may induce EMT in prostate cancer (34).…”

“…9, 10). Previous work by our group and others correlated the activation of NF-kB/interleukin (IL)-6 pathways with docetaxel resistance in CRPC models and in patients (11)(12)(13). Other studies support a role of JUN/AP-1, SNAI1, and NOTCH2/Hedgehog signaling pathways in the development of resistance to docetaxel or paclitaxel (14,15).…”

Imatinib Enhances Docetaxel-Induced Apoptosis Through Inhibition of Nuclear Factor-κB Activation in Anaplastic Thyroid Carcinoma Cells

“…In addition, basal NF-jB activity is often increased in various types of human cancers, which causes chemotherapy resistance (31). Under certain conditions, cytotoxic drugs, such as taxanes, induce NF-jB activation in different types of malignant cells (26,(32)(33)(34)(35)(36). The present data also showed that docetaxel induced NFjB activation and then upregulated antiapoptotic factors in two ATC cell lines, FRO and KTC-2.…”

Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

“…IL-6 is well known as a key downstream target of NF-kB (37). Recently, it was reported that resistance to docetaxel is mediated by increased IL-6 production via NF-kB activation in prostate cancer (38). In addition, it was also reported that autocrine IL-6 production correlates with NF-kB activation in chronic lymphocytic leukemia (CCL) and high IL-6 level is associated with poor prognosis in CCL patients (39).…”