Researchers from the University of Chicago, Fred Hutchinson Cancer Center and other scientific institutions have identified a previously unknown mechanism that allows prostate cancer cells to become more aggressive and resistant to treatment. Targeting a specific RNA molecule may help restore tumors' sensitivity to existing drugs. The findings were published in the journal Nature.
Many prostate tumors depend on androgen receptor activity in their early stages. This protein promotes the growth of cancer cells, which is why treatment often focuses on blocking its activity. However, over time, some tumors adapt: their cells become independent of this mechanism and acquire characteristics of neuroendocrine prostate cancer, a form of the disease that is more difficult to treat.
The scientists discovered that this transition is accompanied by a decrease in the levels of a specific transfer RNA, tRNAArg (UCU)-1. This molecule is involved in protein production, but researchers found that it also helps maintain the identity of tumor cells and preserve their sensitivity to treatment.
The researchers established that a decline in this RNA molecule leads to reduced levels of SMARCC2, a protein involved in organizing DNA and maintaining cellular functions. As a result, cancer cells change their properties, and tumors may become resistant to drugs that target the androgen receptor.
In experiments, restoring the levels of tRNAArg (UCU)-1 or the SMARCC2 protein reactivated androgen receptor signaling and increased the sensitivity of resistant cancer cells to treatment. The scientists also identified two proteins, TARDBP and ZSCAN29, that help maintain the activity of this transfer RNA.
The discovery could provide a basis for developing RNA-targeted treatments, including synthetic molecules designed to replenish the missing RNA. This approach could potentially make it possible to use existing prostate cancer drugs again in patients whose tumors have stopped responding to them.
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