Protein called aPKCι offers potential target for some aggressive cancers

25 October 2013

protein implicated in many aggressive and invasive cancers, atypical protein kinase C iota (aPKCι),can both support and disturb cell polarity and can contribute to cancer if it is present in too high quantities, according to scientists from Cancer Research UK's London Research Institute (now part of the Francis Crick Institute). 

The research suggests that drugs aimed at reducing aPKCι activity may be a promising strategy for treating people with relevant types of cancer. 

Cell polarity refers to the way in which components of cells are restricted to certain regions of the cell. For instance, epithelial cells, which line the surfaces and cavities of our bodies - such as our skin and glands -show cell polarity. They have basal, lateral and apical regions, each of which contain distinct proteins and have distinct functions. 

Epithelial cells are densely packed together like a wall, joined by their lateral membranes, and their cell polarity allows directional transport of molecules across each cell. This enables functions including protection (such as the waterproof nature of our skin) and secretion (such as the secretion of hormones by our glands). 

Loss of polarity in epithelial cells is a hallmark of particularly aggressive and invasive cancers. aPKCι plays a role in maintaining cell polarity but is often expressed in abnormal amounts in cancer where polarity is lost. 

Peter Parker's team and colleagues at the LRI developed lines of cells called MDCK cells that were transformed into cancer cells. In these cells, they altered the expression of cancer-causing genes thought to interact with aPKCi, including one called Ras - a gene that plays a role in many cancers. This led to abnormal polarity. The researchers used these cell lines to test a molecule developed through their drug development programme that inhibits aPKCι.  

Professor Parker said: "Reducing the expression or activity of aPKCι restored normal polarity in  our transformed MDCK cells. This was unexpected because aPKCι activity is known to be necessary to support normal cell polarity. This tells us that aPKCι displays threshold behaviour - too much or too little can both compromise cell polarity. 

"These results are important for two reasons. Firstly, they show that a tumour cell line can be induced to show more normal behaviour - the alterations associated with transforming it as a tumour line do not irreversibly re-programme behaviour of the cells. 

The second reason our findings are important is that they confirm aPKCι as a viable target for therapies in Ras-driven (and possibly other) cancers. Ras mutation is frequent in cancer and there remains a substantial unmet clinical need associated with this. 

Reducing aPKCι activity may be an effective intervention in these cancers."

The paper, Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids, is published in Carcinogenesis.

  • Researchers have uncovered a potential new strategy for targeting the many aggressive and invasive cancers that are characterised by irregular cell polarity, or organisation and alignment of cells, caused by abnormal levels of a protein called atypical protein kinase C iota (aPKCι). 
  • The protein kinase C family is a family of closely related proteins that are involved in a range of functions in the human body. One, called aPKCι, has been implicated in cancer and can cooperate with other cancer-causing proteins. High levels of aPKCι are found in many cancers and this predicts a poor clinical outcome. 
  • The study was funded by Cancer Research UK and The Royal Marsden/ Institute of Cancer Research National Institute for Health Research Biomedical Research Centre.