Macrophage/Cancer Cell Interactions Mediate Hormone Resistance by a Nuclear Receptor Derepression Pathway

Abstract

Defining the precise molecular strategies that coordinate patterns of transcriptional responses to specific signals is central for understanding normal development and homeostasis as well as the pathogenesis of hormone-dependent cancers. Here we report specific prostate cancer cell/macrophage interactions that mediate a switch in function of selective androgen receptor antagonists/modulators (SARMs) from repression to activation in vivo. This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex. TAB2 acts as a sensor for inflammatory signals by serving as a molecular beacon for recruitment of MEKK1, which in turn mediates dismissal of the N-CoR/HDAC complex and permits derepression of androgen and estrogen receptor target genes. Surprisingly, this conserved sensor strategy may have arisen to mediate reversal of sex steroid-dependent repression of a limited cohort of target genes in response to inflammatory signals, linking inflammatory and nuclear receptor ligand responses to essential reproductive functions.

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

“…In U2OS cells the activated form of MEKK1 was detected within the nucleus and the transcriptional coactivator p300 was directly phosphorylated by MEKK1 [44]. In response to IL-1β signalling, MEKK1 was shown to phosphorylate the nuclear TAK binding protein 2 (also known as TAB2), resulting in its conformational change and binding to the nuclear receptor corepressor, thereby leading to a disinhibition of androgen receptor activity [39]. Thus, MEKK1 might exert its effects on insulin gene transcription by acting directly on a transcription factor or accessory factor, without involvement of its downstream kinases.…”

“…IL-1β has been shown to enhance the activity of the mitogen-activated protein kinase kinase kinase [37][38][39]. The effect of IL-1β on the transcriptional activity of the INS promoter, the c-fos gene promoter and the RSV promoter was thus compared with the effect of MEKK1 on the activity of these promoters.…”

Androgen receptor decoy molecules block the growth of prostate cancer

“…For example, TAB2 was recently shown to interact with the AR NTD at residues 179-188 in response to IL-1␤ and induce a switch whereby antiandrogens were able to activate the AR (28). Steroid receptor coactivator-1 was also shown to bind the AR NTD and increase ligandindependent activation of the AR downstream of IL-6 (7).…”

Cancer-related inflammation

“…For carcinoma of the prostate, which is an androgen-dependent tumour, sensitivity to stimulation with hormones is regulated by selective androgen-receptor modulators. The inflammatory cytokine IL-1β, which is produced by macrophages in the tumour microenvironment, converts these receptor modulators from being inhibitory to stimulatory 60 . It has long been known that females are less susceptible to cancer at sites, such as the liver, that are not conventional target organs of sex steroid hormones.…”