New research from the University of Eastern Finland reveals the importance of the glucocorticoid receptor in drug-resistant prostate cancer. The study indicates that limiting the activity of coregulator proteins could potentially prevent the development of drug resistance. Glucocorticoids play a crucial role in regulating essential biological processes by impacting gene encoding.DNA-binding transcription factor known as the glucocorticoid receptor plays a crucial role in medicine due to the powerful anti-inflammatory effects of glucocorticoids. Synthetic glucocorticoids are widely prescribed to treat inflammatory conditions like rheumatoid arthritis and to help cancer patients manage the side effects of cancer therapy. In the treatment of blood cancer, glucocorticoids are essential for inhibiting the growth of cancer cells. Recent research has even revealed additional functions of the glucocorticoid receptor.The research shows that glucocorticoid receptor has a cancer-promoting effect in breast and prostate cancer. In prostate cancer, it can take over the role of the androgen receptor, which is a key factor in the development of this type of cancer, when the androgen receptor is blocked by drug treatment. This means that glucocorticoids help prostate cancer to become resistant to drug treatment.
Docent Ville Paakinaho, an Academy Research Fellow at the University of Eastern Finland, emphasizes the importance of studying the cellular and molecular functions of the glucocorticoid receptor in cancer due to its role in drug resistance and cancer promotion.Akinaho Lab has released two recent in-depth genome-wide sequencing studies on the topic. The first, which was published in Nucleic Acids Research, delved into how the glucocorticoid receptor takes the place of the androgen receptor at the molecular level.
“According to Doctoral Researcher Laura Helminen of the University of Eastern Finland, this study demonstrated that the glucocorticoid receptor is only able to utilize regulatory regions that are already active in prostate cancer cells.”
In simpler terms, drug resistance mediated by the glucocorticoid receptor arises through these regulatory regions, and by impacting the activity of these regions, the negative effects of glucocorticoid receptor activity can be minimized.the promotion of glucocorticoid receptor activity, leading to drug resistance in prostate cancer. Contrary to the researchers’ expectations, inhibiting the activity of FOXA1 actually resulted in an increase in glucocorticoid receptor activity and drug resistance. This unexpected finding suggests that targeting FOXA1 may not be an effective strategy for preventing corticoid resistance in prostate cancer. Bioinformatics analyses identified FOXA1 as a potential target for prevention, but the study’s results indicate that further research is needed to fully understand the role of FOXA1 in drug-resistant prostate cancer.the suppression of the gene for the glucocorticoid receptor, which resulted in increased activity when FOXA1 was blocked.
“Research often uncovers surprises, and that’s what makes it fascinating,” Paakinaho explains.
In drug-resistant prostate cancer, the activity of the glucocorticoid receptor in regulatory regions can be influenced through a different pathway. Coregulator proteins such as EP300 and CREBBP have been identified as an alternate target through which the glucocorticoid receptor impacts gene expression regulation. Small-molecule inhibitors targeting these proteins are being developed by several pharmaceutical companies.
Proteins are being studied in patients as part of ongoing research. In a study by the Paakinaho Lab, researchers looked into ways to stop the effects of the glucocorticoid receptor by inhibiting coregulator proteins. These findings were published in Cellular and Molecular Life Sciences.
“By using a small-molecule inhibitor to silence the EP300 and CREBBP proteins, we were able to effectively prevent the activity of the glucocorticoid receptor in prostate cancer cells,” explained Project Researcher Jasmin Huttunen from the University of Eastern Finland.
This approach helped to inhibit the growth of drug-resistant prostate cancer cells.The researchers discovered that by silencing EP300 and CREBBP, they were able to effectively stop the androgen receptor’s activity, especially in prostate cancer cells with an amplification of the androgen receptor gene, which is present in up to half of patients with advanced prostate cancer. Additionally, the EP300 and CREBBP inhibitor also hindered the activity of FOXA1 while still maintaining its ability to suppress the expression of the glucocorticoid receptor gene. This means that using the EP300 and CREBBP inhibitor could block the activity of FOXA1 without causing drug resistance mediated by the glucocorticoid receptor.The study found that inhibiting the activity of both the androgen and the glucocorticoid receptor was mainly due to the restriction of FOXA1 activity. This suggests that targeting coregulator proteins in treatment could also be effective in untreated prostate cancer. The research was funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland.
