A novel approach to combat therapy-resistant prostate cancer

A recent study under the leadership of scientists from the Florida campus of The Scripps Research Institute (TSRI) explains clearly about a signaling circuit in cells that can lead to treatment resistance in prostate cancer. The researchers discovered that targeting the components of this circuit blocks the development of advanced prostate cancer. The study, headed by TSRI Associate Professor Jun-Li Luo, was released online ahead of print in the journal Molecular Cell.

A novel strategy to battle Prostate Cancer

Prostate cancer is one of the most common types of cancer in America; it affects one in six American men according to the American Cancer Society. It is the second-leading deadliest cancer after lung cancer in American men.

Right now, the most efficient treatment for advanced prostate cancer is to deprive the cancer of what feeds it — androgen hormones such as testosterone. Sadly, almost all patients finally become resistant to this treatment, leaving doctors with no choices to counteract the unavoidable.

The recent study demonstrates that a “constitutively active” signaling circuit can stimulate cells to grow into tumors and develop therapy resistance in advanced prostate cancer. A cell signaling pathway with constitutive activity needs no binding partner or ligand to activate; alternatively, the signaling circuit constantly triggers itself.

This signaling circuit, which contains of the protein complex I?B?/NF-?B (p65) and many other molecules, manages the expression of stem cell transcription factors known as the proteins that conduct the conversion of genetic information from DNA to RNA, which fuel the invasive growth of these resistant cancer cells.

“The fact obtained from the finding that, the constitutive activation of NF-kB in the circuit is not dependent on traditional trigger opens the door for potential therapeutic options,” remarked Luo.

Blocking NF-?B activity

NF-kB is known to have significant roles in cancer development, and it is considered as one of the most common key targets for cancer therapy. But the utilization of NF-?B inhibitors in the treatment of cancer is made difficult by severe side effects associated with immunosuppression from random inhibition of NF-?B in normal immune cells.

Luo mentioned that targeting the other non-I?B?/NF-?B components in this signaling circuit would prevent the suppression of NF-?B in normal immune cells whilst keeping the potent anti-cancer efficiency.

Other than I?B?/NF-?B, the signaling circuit contains the microRNA miR-196b-3p, Meis2 and PPP3CC. Although miR-196b-3p supports the development of tumor, Meis2, which is an important developmental gene in mammals, can disturb the circuit when overexpressed. The protein PPP3CC can block NF-?B activity in prostate cancer cells.

“Blocking this circuit by targeting any of its individual components inhibits the expression of these transcription factors and remarkably weaken therapy-resistant prostate cancer,” stated TSRI Research Associate Ji-Hak Jeong, who is the first author of the study.

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