Image supplied by WEHI. Calmodulin binds to PSKH1 (in grey) to 'switch on' PSKH1 activity. Reticulocalbin binds to PSKH1 to 'switch off' PSKH1 activity.
Melbourne-based scientists have, for the first time, discovered how to "switch off" a molecule which is one of the top culprits behind prostate cancer, and is also linked to lung and kidney cancers.
The "dark molecule" - meaning it's understudied - is known as 'Protein Serine Kinase H1' (PSKH1) and is associated with tumour progression and metastasis. However, until now, how it does this has been unknown.
In this study, published in the journal PNAS and led by the Monash Institute of Pharmaceutical Sciences (MIPS) and WEHI, the team uncovered the way in which PSKH1 is activated (or "switched on") and, importantly, how it is switched off.
In the case of PSKH1, which is a 'signalling molecule', the researchers found that when it binds to a protein called 'Calmodulin' PSKH1 is "switched on" and when it binds to a protein called 'Reticulocalbin' it is "switched off".
Joint senior author, Dr John Scott from MIPS, describes this signalling activity as "a balancing act within our cells."
"Tumours form because cells ignore normal signals that tell them it's time to stop growing, or that it's time to die. When a signalling molecule, such as PSKH1, interacts with certain proteins on a cell surface, this binding triggers a chain of events that can amplify the cell activity and lead to the formation of tumours," Dr Scott said.
"Now that we know more about the proteins driving the 'on' and 'off' status of PSKH1, we can start to develop new drugs that target this molecule and, ultimately, improve therapies for prostate and other cancers."
In 2024, prostate cancer was estimated to be the most commonly diagnosed cancer for males and for Australia overall. Treatments such as hormone therapy and chemotherapy can be effective, yet the side effects can be debilitating.
Joint senior author, Professor James Murphy from WEHI, said the team's goal is to harness this new information to develop better, more targeted therapeutic approaches.
"Switching off PSKH1 essentially means being able to stop the progression of implicated cancers in their track, and thereby this new information opens up a whole new world of potential when it comes to developing new drugs," Professor Murphy said.
"From here, our goal is to explore how we can start to develop new effective therapies, with less side effects."
Excitingly, understanding the mechanisms of how to switch PSKH1 on and off can also be applied to other molecules within the same family, broadening the potential of the study's findings to other cancers and diseases.
Research
Source of information: Proceedings of the National Academy of Sciences
Christopher R. Horne1,2,3*, Toby A. Dite1,2, Samuel N. Young1, Lucy J. Mather1, Laura F. Dagley1,2, Jared L. Johnson4,5,6, Tomer M. Yaron-Barir4,7,8, Emily M. Huntsman4,7, Leonard A. Daly9,10, Dominic P. Byrne9, Antonia L. Cadell11, Boaz H. Ng11, Jumana Yousef1,2, Dylan H. Multari1,2, Lianju Shen1, Luke M. McAloon3,12,13, Gerard Manning14, Mark A. Febbraio3, Anthony R. Means15, Lewis C. Cantley 4,5,6, Maria C. Tanzer1,2, David R. Croucher11,16, Claire E. Eyers9,10, Patrick A. Eyers9, John W. Scott3,13,17,*†, James M. Murphy1,2,3,*†
DOI: https://doi.org/10.1073/pnas.2420961122
Declaration
The study was supported by the National Health and Medical Research Council of Australia; the Australian Research Council; the CASS Foundation; the Victorian State Government Operational Infrastructure Support Scheme; and United Kingdom Research and Innovation Biotechnology and the Biological Sciences Research Council.
