Protein kinase C (PKC) enzymes control the function of other proteins through the phosphorylation of hydroxyl groups of amino acid residues on proteins. They have been shown to play an important role in cell survival and proliferation as well as cell migration. Due to those roles, PKC was thought for many years to promote the development of tumors and many researchers have worked on developing drugs that inhibit PKC to help with the treatment of cancer.
Alexandra Newton, PhD, professor in the Department of Pharmacology at UC San Diego School of Medicine conducted an important study in 2015 which revealed PKC actually suppresses the formation of tumors, which suggested that drugs should instead be developed to boost PKC levels in cells.
Newton and her team of researchers at UC San Diego School of Medicine have now shown that another enzyme is also involved in the process: PHLPP1. PHLPP1 was discovered to play an important role in controlling the level of PKC in cells. Whenever PKC levels are elevated, PHLPP1 is involved in the destruction of PKC. The amount of PHLPP1 in cells determines the level of PKC. This has implications for patients with pancreatic cancer.
The UC San Diego School of Medicine researchers collaborated with Gordon Mils PhD at the OHSU Knight Cancer Institute and analyzed their protein tumor database. They discovered out of the 105 pancreatic tumors included in the database, those with high levels of the enzyme PHLPP1 also had low levels of the enzyme PKC. Patients with low levels of PKC had a poor survival rate. None of the low PKC patients survived more than 5.5 years. Half of patients who had low levels of PHLPP1 and high levels of PKC survived much longer.
The discovery could lead to a new method of treating pancreatic cancer. Rather than try to increase the level of PKC, a better option may be to inhibit PHLPP1 to bring PKC levels up, and by doing so, improve survival rates. The relative levels of PHLPP1 and PKC could also be used by clinicians in diagnostic tests to determine the prognosis for a patient.
The research team is now attempting to identify compounds that inhibit PHLPP1 in pancreatic cancer cells in the lab to determine whether it is possible to inhibit PHLPP1to raise PKC levels.
The research is detailed in the paper – Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer – which was recently published in the journal Molecular Cell. DOI: 10.1016/j.molcel.2019.02.018