Attacking Molecular Circuitry May Help Combat Castration-Resistant Prostate Cancer

A new study is suggesting it may be possible to shut down the circuits that drive the high tumorigenicity of prostate cancer cells leading to castration-resistant prostate cancer (CRPC). The researchers report in the journal Molecular Cell that targeting the components of specific circuits may lead to the development of novel less toxic CRPC therapeutic strategies.  

Currently, the most effective treatment for advanced prostate cancer is androgen deprivation therapy (ADT), but virtually all men eventually develop resistance. The new study shows that a “constitutively active” signaling circuit can trigger cells to grow into tumors and drive therapy resistance. A cell signal pathway with constitutive activity requires no ligand to activate; instead the signaling circuit continually activates itself.

This signaling circuit, which is composed of the protein complex IκBα/NF-κB (p65) and several other molecules, controls the expression of stem cell transcription factors, fueling the aggressive growth of these resistant cancer cells. “The fact that the constitutive activation of NF-kB in the circuit is independent of traditional activation opens the door for potential treatment options,” said lead study author Professor Jun-Li Luo, PhD, who is an associate professor at the Florida campus of the Scripps Research Institute (TSRI), Jupiter, Fla.

NF-kB plays important roles in cancer development. However, the use of NF-kB inhibitors in treating cancer has been hampered by severe side effects related to immunosuppression caused by indiscriminate inhibition of NF-kB in healthy immune cells. Luo noted that targeting the other non-IκBα/NF-κB components in this signaling circuit would avoid the suppression of NF-κB in healthy immune cells while keeping the potent anticancer efficacy.

In addition to IκBα/NF-κB, the signaling circuit includes the microRNA miR-196b-3p, Meis2, and PPP3CC. While miR-196b-3p promotes tumor development, Meis2 (an essential developmental gene in mammals) can disrupt the circuit when overexpressed. The protein PPP3CC can inhibit NF-κB activity in prostate cancer cells.  Study co-author Ji-Hak Jeong, who is a research associate at TSRI, said disrupting this circuit by targeting any of its individual components blocks the expression of transcription factors and significantly impairs therapy-resistant prostate cancer.

These findings are based on studies using prostate cancer allograft mouse models to mimic human CRPC development. If further studies are confirmatory, this new insight into the bona fide mechanisms underlying castration resistance may provide the foundation for the development of new CRPC therapeutic strategies, according to the investigators.