In a new study, researchers from the University of Texas Southwestern Medical Center discovered an Achilles’ heel of ovarian cancer and new biomarkers that may indicate which patients are the best candidates for potential new therapies. Related research results are published online in the Cell journal.
Many scientists are trying to find cancer dependence by asking why cancer cells amplify a gene, increase the level of a protein, or up-regulate a key cellular pathway. These changes provide cancer a selective advantage, moreover, they can also become a fatal weakness-if these changes are blocked, it will kill cancer or prevent its growth.
Researchers have discovered that ovarian cancer will amplify a large number of enzymes that make NAD+: NMNAT-2. NAD+ is a substrate of a family of enzymes called PARP. PARP uses ADP-ribose from NAD+ to chemically modify proteins. In this new study, the Kraus team discovered that as a member of the PARP family, PARP-16 uses NAD+ to modify ribosomes, the protein synthesis machinery in cells.
One challenge facing this research is that the single ADP-ribose group attached to the protein is difficult to detect. The research team overcomes this problem by developing a synthetic single (ADP-ribose) detection reagent fused with natural protein domains, which can be used to detect ADP-ribosylated proteins in cells and patient samples. In cooperation with other teams, the researchers used this single (ADP-ribose) test reagent to screen samples from human ovarian cancer patients to identify those with lower or higher levels of single (ADP-ribose).
Studies have shown that when the ribosomes in ovarian cancer cells are mono-(ADP-ribose), this modification changes the way they translate mRNA into protein. Ovarian cancer amplifies NMNAT-2 to increase the level of NAD+ required for PARP-16 to mono(ADP-ribosylate) ribosomes, giving them a selective advantage by allowing them to fine-tune translation levels and prevent toxic protein aggregation. But this selective advantage has also become their Achilles’ heel. They are addicted to NMNAT-2, so inhibiting or reducing NMNAT-2 will inhibit the growth of cancer cells.
Thi study identified mono (ADP-ribose) and NMNAT-2 as potential biomarkers for ovarian cancer, which may allow clinicians to determine which ovarian cancer patients may respond well and which will not. If PARP-16 inhibitors that block mono(ADP-ribosylation) are developed, more ovarian cancer patients may get better.
The medical community has achieved great success in developing PARP-1 inhibitors approved by the U.S. Food and Drug Administration (FDA), and PARP-16 inhibitors are also likely to appear. No PARP-16 inhibitor has entered clinical trials, but laboratories in academia and the pharmaceutical industry are developing specific and potent inhibitors that target PARP-16. Such drugs may be effective treatments for ovarian cancer.
The research is not just a huge advancement in basic science. It has great potential for clinical researchers and cancer care practitioners because it shows a biomarker and a pathway that future drugs may target.
Reference:
- Sridevi Challa et al. Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers. Cell, 2021, doi:10.1016/j.cell.2021.07.005.