aPKCλ/ι promotes growth of prostate cancer cells in an autocrine manner through transcriptional activation of interleukin-6

Abstract

Understanding the mechanism by which hormone refractory prostate cancer (HRPC) develops remains a major issue. Alterations in HRPC include androgen receptor (AR) changes. In addition, the AR is activated by cytokines such as interleukin-6 (IL-6). Atypical protein kinase C (aPKC/) has been implicated in the progression of several cancers. Herein, we provide evidence that aPKC/ expression correlates with prostate cancer recurrence. Experiments in vitro and in vivo revealed aPKC/ to be involved in prostate cancer cell growth through secretion of IL-6. Further, aPKC/ activates transcription of the IL-6 gene through NFB and AP-1. We conclude that aPKC/ promotes the growth of hormone independent prostate cancer cells by stimulating IL-6 production in an autocrine manner. Our findings not only explain the link between aPKC/ and IL-6, implicated in the progression a variety of cancers, but also establish a molecular change involved in the development of HRPC. Further, aPKC/ expression might be a biomarker for prostate cancer progression.

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

“…In particular, both aPKC/ and aPKC have been shown to interact with and activate IKK␤ (22,54). Prior studies have also demonstrated that activated NF-B induces IL-6 to promote malignancy (23,55). These reports are consistent with our data, which indicate that loss of PAR3 induces preferential phosphorylation of IKK␤ (Fig.…”

“…Moreover, the magnitude of IL-6 induction that we observe in NICD1-mMEC cells (Figs. 4 (A and B), 5A, and 6E) is similar to the IL-6 induction reported following activation of aPKC and NF-B in a prostate cancer model (23).…”

“…aPKC/ and aPKC interact with and activate multiple components of the NF-B pathway (39). aPKC/-mediated activation of NF-B induces IL-6 production in prostate cancer (23), and silencing of PAR3 can activate NF-B signaling in human intestinal epithelial cells (40). Moreover, the degree of IL-6 induction reported in prostate tumor cells following aPKC-mediated NF-B activation is similar to what we have observed in mammary cells (23).…”

“…aPKC/-mediated activation of NF-B induces IL-6 production in prostate cancer (23), and silencing of PAR3 can activate NF-B signaling in human intestinal epithelial cells (40). Moreover, the degree of IL-6 induction reported in prostate tumor cells following aPKC-mediated NF-B activation is similar to what we have observed in mammary cells (23). To test whether activation of STAT3 requires NF-B signaling in out system, we first treated NICD1-mMEC/shPAR3 cells with two chemical inhibitors of NF-B, JSH-23 and caffeic acid phenethylester (CAPE).…”

Activation of Nuclear Factor κB (NF-κB) in Prostate Cancer Is Mediated by Protein Kinase C ϵ (PKCϵ)

“…Although many studies highlighted the relevance of the atypical PKCs and as NF-B modulators (14,15), Diacylglycerol (DAG)/phorbol ester responsive PKCs also emerged as potential modifiers of NF-B signaling (16 -18). Both classical/conventional cPKCs (␣, ␤, and ␥) and novel nPKCs (␦, ⑀, , and ) have been implicated as regulators of apoptosis, survival, differentiation, mitogenesis, and transformation in a strict cell-type dependent manner.…”