Deciphering the molecular mechanism of naphthoquinone-induced Sirtuin 7 inhibition: a step forward in development of new anticancer drugs

The naphthoquinones and their hydroxylated derivatives have a wide variety of pharmacological actions, including antioxidant, antibacterial, antiviral, anticancer, antimalarial, and antifungal properties. Molecular activities of naphthoquinones in cells are either through generating oxidative stress through reactive oxygen species (ROS) formation and directly engaging with conventional therapeutic targets in a non-oxidant method. Naphthoquinones also are toxicologically intriguing since they exist in the atmosphere as bioactive environmental pollutants. In addition to passive exposure to naphthoquinones, there is significant exposure to its precursor naphthalene, the most abundant polynuclear aromatic hydrocarbon in ambient air. Because naphthalene is physiologically metabolized into naphthoquinones, inhaling it may potentially expose individuals to naphthoquinones.

Sirtuins were first reported as transcription repressors in yeast, but they are now known to exist in bacteria and higher eukaryotes. Seven NAD⁺ dependent deacetylase sirtuins have been described in mammals (SIRT1-7) with different substrate preferences, enzymatic activities, cellular locations, and targets. All sirtuins share a common conserved NAD⁺-binding domain but differ in their amino and carboxy-terminal regions that contribute to their catalytic activity and specific locations within the cell. Sirtuins are thought to play a significant role in cell response to a range of outside stimuli, such as oxidative or genotoxic stress, and are also essential for cell metabolism. SIRT7 interacts with both the promoter and the transcribed regions of rDNA genes. This sirtuin mainly deacetylates lysine K18 of histone H3, a deacetylation linked to the silencing of tumor suppressor genes. Regarding cancer, SIRT7 is generally considered an oncogene. It can thereby support the cancer phenotype by inhibiting tumor suppressor expression.

It is still unknown wether SIRT7 plays a role in balancing ROS generation and antioxidant defenses. In a new research paper published in the Journal of Cell Science, Université Paris Cité scientists: Dr. Valentina Sirri, Dr. Jérémy Berthelet, Dr. Oliver Brookes, and Dr. Pascal Roussel identified the detailed molecular mechanism of action of naphthoquinones in cervical cancer cells (HeLa cells) and how naphthoquinones specifically menadione, and plumbagin inhibited the nucleolar SIRT7 in vitro. According to the authors menadione inhibits DNA repair by inhibiting SIRT7-dependent recruitment of the DNA damage response factor 53BP1 to DNA double-strand breaks. Although menadione and plumbagin directly reduce SIRT7 activity in vitro, the authors confirmed that the effects seen in vivo are not due to protein tyrosine phosphatase inhibition. The oxidizing agent tBHP did not reproduce the effects of menadione or plumbagin, and the inhibition of SIRT7 activity did not appear to be connected to oxidative changes.

On the other hand, the menadione-induced effects on rDNA transcription, pre-rRNA processing, and development of etoposide-induced 53BP1 foci were progressively reversed in their study. This discovery, however, does not call into question the irreversibility of SIRT7 inhibition. Indeed, as demonstrated by the development of etoposide-induced 53BP1 foci, recovery occurs only when protein synthesis is feasible, i.e., in the absence of the protein synthesis inhibitor cycloheximide. Therefore, the restoration of SIRT7 activity is most likely attributable to freshly produced proteins rather than the removal of SIRT7 inhibition. The research team reported that arylation processes are required for menadione or plumbagin-induced SIRT7 inhibition and accordingly, this inhibition of SIRT7 activity decreased when the thiol reducing agent N-acetyl-L-cysteine was used to prevent sulfhydryl arylation by menadione or plumbagin. Furthermore, the authors postulated that menadione or plumbagin-induced inhibition of SIRT7 depends on arylation reactions, specifically the arylation of catalytic cysteine residues and that the inhibition observed for SIRT7 can be generalized to all sirtuins due to the conserved NAD-dependent catalytic domain.

Finally, the authors demonstrated that SIRT7 inhibition may be critical in identifying menadione or plumbagin as anti-tumor drugs that may be utilized in conjunction with other anti-tumor approaches. Due to the oncogenic role of SIRT7 in different tumor types, a strong effort in the future should be devoted to identify robust SIRT7 inhibitors that could be used as new clinically relevant anticancer therapeutic agents.