Understanding how cellular stress contributes to cell survival
By Amanda Chase, PhD
Cancer is a result of unusual cell growth that results in more abnormal cells, damaged cells surviving when they should not, and new cells forming when they should not. The extra cells may form tumors, or masses of tissue. Unfortunately, one in three people will receive a cancer diagnosis in their lifetime, making this a critical area for finding successful treatments and preventative measures.
In a recent Cell Chemical Biology publication, researchers identified a small molecule that works to simultaneously target two pathways of therapeutic interest in cancer – Wnt and p53. The new small molecule, called PAWI is both a p53 activator and Wnt inhibitor. The team was led by Mark Mercola at the Cardiovascular Institute and Department of Medicine at Stanford University and John Cashman at the Human BioMolecular Research Institute in San Diego, and co-first authors Jiongjia Cheng in the Cashman lab and Masanao Tsuda formerly in the Mercola lab at the Sanford-Burnham-Prebys Medical Institute in La Jolla, CA.
It was puzzling how a compound could both activate p53 and inhibit Wnt. The p53 protein regulates cell division, which is necessary for proper development and proliferation of cells. Wnt is important for cell movement and differentiation. Using the PAWI compound, the team traced a kinase signaling cascade that connects cellular stress, such as occurs when a cell has damaged DNA or otherwise cannot replicate, to the control of Wnt signaling and p53. “The finding that cellular stress is linked to Wnt responsiveness is important because it explains why stressed cells do not regenerate or heal tissue damage” explains Dr. Mercola.
This finding has important implications for understanding the influence of stress signaling on cell renewal and tissue development and on small molecule anticancer therapies. Wnt and p53 are often deranged in cancer. Wnt promotes certain tumors, while loss of p53 causes unbridled cancer cell replication. By mimicking cellular stress, the PAWI compound potently blocks Wnt responsiveness and activates p53; thus providing two powerful anti-cancer effects. Its selectivity for both could be greater than that achieved with current anticancer agents. This is important because few Wnt inhibitors have progressed to clinical trials for cancer as they are suggested to lack sufficient selectivity. A prior paper published by the team (Cancer Research, 2018) showed that PAWI is effective at treating an animal model of colorectal cancer. The discovery of PAWI’s mechanism of action should broaden the scope of candidates that can be utilized as cancer therapeutics.
Other Stanford Cardiovascular Institute affiliated authors include Isaac Perea-Gil, Arne Bruyneel, Jaechol Lee, Nirmal Vadgama, Justine Quach, Wesley McKeithan, Joseph Wu, and Ioannis Karakikes. They were joined by medicinal chemists at the Human BioMolecular Research Institute, Stanford-Burnham-Prebys Medical Discovery Institute, University of California, San Diego, Christian-Albrechts University of Kiel, Germany, and University of Washington.