Activator of Sirt6 exerts antitumor activity in pituitary neuroendocrine tumors

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial neuroendocrine tumors. Surgical resection is the first choice for most subtypes of PitNETs. However, radical removal of invasive tumors remains challenging. A novel pharmacological therapy is objectively needed. Sirtuin 6 (Sirt6) is a member of the NAD⁺-dependent class III deacetylase sirtuin family, which plays a key role in tumorigenesis in many tumors. However, the role of Sirt6 and its activator in PitNETs is still unclear.

In the study, we investigated the expression of Sirt6 and the antitumor effect of the Sirt6 activator MDL-800 in PitNETs.

The expression of Sirt6 was detected in PitNET and cell lines by RNA-seq, immunohistochemistry, and western blotting. To test Sirt6 and its activator MDL-800, the cell viability, clone formation, and xenograft experiment were conducted. Autophagy was evaluated by microscopy and western blotting analysis. The efficacy of MDL-800 in the human primary PitNET cells was also investigated by the cell viability assay.

Low expression of Sirt6 was found in PitNET tissues and two pituitary cell lines. Sirt6 inhibited cell proliferation and clone formation. Treatment with MDL-800 suppressed cell growth in vitro and in vivo. Further mechanistic studies showed that MDL-800 could lead to lethal autophagy and exert an antitumor effect in human primary PitNET cells.

Our results suggest that activation of Sirt6 by its selective activator MDL-800 is a promising therapy for PitNETs.