A research group led by scientists at The Scripps Research Institute (TSRI) Florida campus has identified a novel approach to dealing with prostate cancer that involves blocking a newly discovered, constitutively active signaling circuit that plays a role in the development of androgen treatment resistance and aggressive tumor growth. Studies by TSRI associate professor Jun-Li Luo, Ph. D., M. M., and colleagues have found that inhibiting components in this routine can hold back the progression of therapy-resistant advanced prostate cancer.
Androgen therapy is the most effective treatment intended for advanced prostate cancer, but nearly all patients will ultimately develop resistance. The signaling circuit identified by Doctor Luo and colleagues comprises the protein complex Iκ Bα /NF-κ B (p65), miR-196b-3p, Meis2, and PPP3CC, and controls the expression of stem cell transcribing factors that drive tumorigenicity. Being constitutively active, the particular circuit “ is not dependent on the activation of some other traditional IKKβ /NF-κ B pathways that are important within normal immune responses, ” the authors write within their paper “A Constitutive Intrinsic Inflammatory Signaling Circuit Made up of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Malignancy Castration Resistance, ” published in Molecular Cell. This particular “ opens the door for potential treatment options, ” Doctor Luo comments.
NF-κ B is an important target for cancer therapy, but NF-κ B blockers can also cause severe side effects related to immunosuppression that comes from the unwanted inhibition of NF-κ B in regular immune cells. The TSRI research indicates that focusing on the non-Iκ Bα /NF-κ B components in the recently discovered signaling circuit would avoid the suppression of NF-κ B in normal immune system cells, without affecting anticancer potency.
“Disrupting this circuit by concentrating on any of its individual components blocks the expression of the transcription factors and significantly impairs therapy-resistant prostate malignancy, ” suggests TSRI research associate Ji-Hak Jeong, the very first author of the study. “ Our studies present deeply insight into the bona fide mechanisms underlying castration resistance and supply the foundation for the development of CRPC [castration-resistance prostate cancer] healing strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κ B inhibition in normal cells, ” the writers conclude.