The ‘ribosomal stress (RS)-p53 pathway’ is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. Inosine monophosphate (IMP) dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2.
Cancer develops when cells lose the ability to control their own growth. About half of cancerous tumors carry a dysfunctional version of a protein called p53, while the other half have defects in proteins that are important for p53's production and function. When a healthy cell is exposed to damaging chemicals or agents, the p53 protein triggers responses that are aimed at repairing the damage. However, if these attempts fail, p53 causes the damaged cell to essentially destroy itself.
As defects in p53-controlled processes cause cells to grow unrestrictedly and can lead to cancer, it is a very attractive target for cancer therapies. Cancer drug developments have focused on both targeting p53 directly and targeting the proteins that work with p53. Two proteins called Mdm2 and SIRT1 are of particular interest. Mdm2 binds to, inactivates, and leads to the degradation of p53. SIRT1 can modify p53 and make it more accessible to Mdm2, and is often found in very high levels in cancer cells.
In 2012, researchers identified Inauhzin as a small molecule that could potentially be used to treat tumors that still have a functional version of the p53 protein. Inauhzin was thought to work by inhibiting SIRT1, which increases p53 levels—probably through its effects on Mdm2. This restores the cell's ability to control its growth and to die if it is irreparably damaged. However, not all of this small molecule's effects on cells can be explained by its interaction with SIRT1.
Now Zhang et al., including some of the researchers involved in the 2012 work, have investigated whether Inauhzin also interacts with other proteins in the cell; and Inauhzin was revealed to bind an enzyme called IMPDH2. This enzyme is involved in making GTP—a small molecule that is involved in many important processes in living cells. Zhang et al. demonstrated that Inauhzin's effect on the IMPDH enzyme triggered a response that did not involve the SIRT1 protein, and that ultimately led to a decrease in Mdm2 activity and restored p53 activity.
Cancer treatments often include a combination of drugs that target different proteins with the goal of reducing the likelihood of a tumor becoming resistant to the treatment. Inauhzin's effect on two different proteins that lead to p53 activation not only increases its potency, but also makes it less likely that drug resistance will develop.