Molecular Relative of p53 Tumor-suppressor Protein also Helps Cancer Cells Thrive
The protein TAp73 shares extensive common gene sequences with the tumor-suppressor protein p53, and previous studies have suggested that it may function similarly to p53 to prevent tumor formation. However, unlike p53, the most commonly mutated gene in human tumors, TAp73 is rarely mutated and is instead frequently overexpressed in a wide range of human tumors, including breast, colon, lung, stomach, ovarian, bladder, liver, neuroblastoma, and glioma, as well as leukemias.
In a recent study published in Nature Cell Biology, Xiaolu Yang, PhD, Professor of Cancer Biology at the Perelman School of Medicine, University of Pennsylvania, and the Abramson Family Cancer Research Institute, and colleagues found that TAp73 supports the proliferation of human and mouse tumor cells.
They also identify an important mechanism by which TAp73 gives tumor cells a growth advantage: It activates the expression of an enzyme called glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting molecule of the pentose phosphate pathway. The pentose phosphate pathway is important for both biosynthesis and antioxidant defense, and tumor cells need this pathway for their high rate of replication.
Study Details
The study was led by Peng Jiang, PhD, and Wenjing Du, PhD, two postdoctoral fellows in Dr. Yang's lab. They and the rest of the team found that by stimulating G6PD, TAp73 increases pentose phosphate pathway activity and directs the sugar glucose to pathways for synthesizing macromolecules for replication and detoxifying reactive types of oxygen molecules to protect cells from harm.
The team also found that the decrease in replication in cells without TAp73 can be rescued by either enforced expression of G6PD, or adding nucleosides and a reactive oxygen species scavenger to mop up these deleterious molecules, two outcomes of the pentose phosphate pathway. These data provide the evidence that stimulating the pentose phosphate pathway is a main proliferative effect of TAp73.
This is the first evidence that TAp73 is needed for tumor growth, as seen in the mouse and human colon, lung, and other cancers studied.
A previous study led by Drs. Jiang and Du found that p53 has the exact opposite effect on the pentose phosphate pathway in that it physically binds to and inhibits G6PD, dampening synthesis of molecules and cell reproduction by forcing the cell to take up less glucose. The opposing effect of two members of the p53 family on G6PD underlines the importance of the enzyme and the pentose phosphate pathway in tumor cells.
“These findings establish a critical role for TAp73 in regulating metabolism and connect TAp73 and the pentose phosphate pathway to cancerous cell growth,” said Dr. Yang.
Potential Target in G6PD Enzyme
The prevalence of p53 inactivation and TAp73 upregulation indicates that modulating the pathways that these two proteins control could bring substantial benefit to tumor therapy. However, targeting these pathways has proven to be difficult as most proteins in the p53 and TAp73 pathway operate via protein-protein interactions, which are generally poor drug targets.
In contrast, metabolic enzymes are among the best drug targets. The identification of G6PD as an enzyme that becomes hyperactive in tumors with p53 inactivation and/or TAp73 overexpression, two of the most common genetic alterations in cancer cells, suggests that inhibition of this enzyme, or its related enzymes in the pentose phosphate pathway, may be highly beneficial for the therapy of a wide range of tumors.
This work was funded by the National Cancer Institute (CA088868 and GM060911) and the Department of Defense (W81XWH-10-1-0468) and grants from the University of Science and Technology of China.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
