Unexpected opposing effects of two protein kinases on prostate cancer revealed

 26 September 2018   Research News

In the UK, about 1 in 8 men will get prostate cancer at some point in their lives (Prostate Cancer UK).

Research by the Cellular Stress group, that will be published in Cancer Research later this year, highlights key proteins which hold the potential to treat prostate cancer.

Current treatments focus on either activating or inhibiting key proteins within cells that are known to supress or cause tumour growth. It is hoped that greater understanding of these interactions will lead to improvements in future treatments.

The researchers from the MRC LMS developed novel genetic mouse models to study the roles of two protein kinases in prostate cancer: CAMKK2, a protein coding gene upregulated in the disease and, AMPK. AMPK is an important enzyme that senses energy status within a cell and is the main enzyme of focus in the Cellular Stress group, led by Dave Carling.

At the time the research began, in 2012, the role of AMPK in prostate cancer was controversial, whereas CAMKK2, an upstream activator of AMPK had been shown to be overexpressed in human prostate cancer.

The paper shows that CAMKK2 and AMPK have opposing effects on prostate cancer development, both in cell lines and importantly in vivo. The key finding in the paper was that CAMKK2 induces prostate cancer development and that this occurs independently of AMPK activation. Both deletion or inhibition of CAMKK2 were found to significantly supress prostate cancer development. The paper also shows that AMPK deletion induces prostate cancer, suggesting that AMPK activation would supress prostate cancer development. The next step is to validate that AMPK activation does supress tumour development in vivo.

Speaking about the findings Lucy Penfold, first author and Research Associate in the Cellular Stress group, shared her thoughts,

Lucy Penfold and Dave Carling at the MRC LMS

“I don’t think any of us really knew what we were expecting to see, I think if anything we thought that CAMKK2 and AMPKB1 knock out prostate cancer mouse models would have the same phenotype when in fact they had the opposite phenotype so that was really interesting.”

The possibility of a new combined therapeutic approach is something that the team will be testing through a three-year, £235,582 grant from Prostate Cancer UK. This grant will allow them to further investigate and validate CAMKK2 inhibition and AMPK activation in reducing prostate cancer both individually and in combination.

The initial research in the publication was undertaken during Lucy’s PhD at the Institute. She has recently returned to work on the Prostate Cancer UK grant as a postdoc and discussed the PhD and postdoc/research process,

“Throughout my PhD and into my postdoc I have been lucky to be able to make the most of all the resources available to MRC researchers and to have the support of everyone in the team. There have obviously been huge ups and downs but it’s fantastic to have it published and to receive the PCUK grant. I’m really excited to continue the work.”