Concentrating on the MAPK4 enzyme could possibly be a possible new technique to combat prostate most cancers
The fight against late-stage prostate cancer may have identified a possible new strategy to combat this deadly disease. Research by Baylor College of Medicine in the Journal of Clinical Investigation shows that the enzyme MAPK4 works together to activate androgen receptor (AR) and AKT, molecules at the core of two cellular signaling pathways known to promote prostate cancer growth and resistance to standard therapy .
Importantly, the simultaneous inhibition of MAPK4 inactivated both AR and AKT and stopped cancer growth in animal models. The results suggest that targeted treatment for MAPK4 in human prostate cancer may represent a novel therapeutic strategy for this disease, which is the second leading cause of death in American men.
“Scientists already knew that both the AR and AKT pathways can drive prostate cancer,” said author Dr. Feng Yang, Assistant Professor of Molecular and Cell Biology and a member of the Dan L Duncan Comprehensive Cancer Center in Baylor. “One complication of targeted treatment for AR (e.g. medical castration therapy, including the most advanced drugs such as enzalutamide, apalutamide, and abiraterone) or AKT is that there is cross-talk between these pathways. When AR is inhibited, there is crosstalk ACT activated. And vice versa, so it is complex to address these avenues for controlling cancer growth. “
In previous work, the Yang laboratory examined the little-known enzyme MAPK4.
One interesting aspect of MAPK4 is that it is quite unique in that it doesn’t work like traditional MAPK enzymes. To the best of our knowledge, we are one of the few groups studying MAPK4 and the first to uncover its critical role in human cancers. “
Dr. Feng Yang, Assistant Professor of Molecular and Cell Biology, Baylor College of Medicine
In their previous study, Yang and colleagues discovered that MAPK4 can trigger the AKT signaling pathway not only in prostate cancer, but also in other cancers such as lung and colon cancer.
In the current study, the researchers found that MAPK4 also activates the AR signaling pathway by improving the production and stabilization of GATA2, a factor that is critical for the synthesis and activation of AR.
Further experiments showed that MAPK4 triggered the concerted activation of AR and AKT pathways through independent mechanisms. This promoted prostate cancer growth and resistance to castration therapy, a standard medical treatment for advanced / metastatic prostate cancer. Importantly, the genetic degradation of MAPK4 reduced activation of AR and AKT pathways and inhibited the growth of prostate cancer in animal models, including castration-resistant growth. The researchers believe that the breakdown of MAPK4 could also reduce the growth of other cancers that MAPK4 is involved in.
“Our results suggest the possibility that regulation of MAPK4 activity could lead to a novel therapeutic approach for prostate cancer,” said Yang. “We are interested in finding an inhibitor of MAPK4 activity that could help improve the treatment of prostate cancer and other cancers in the future.”
Baylor College of Medicine
Shen, T. et al. (2021) MAPK4 promotes prostate cancer through the concerted activation of the androgen receptor and AKT. Journal of Clinical Investigation. doi.org/10.1172/JCI135465.