The STK33/mTORC1/S6K1/HIF-1α signalling axis drives glycolysis and progression in pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours (PanNETs) are characterized by metabolic reprogramming, but the underlying mechanisms driving their progression remain poorly understood. Therefore, we investigated whether serine/threonine kinase 33 (STK33) promotes PanNET growth and aerobic glycolysis via mTORC1/S6K1/HIF-1α signalling.

PanNET specimens and adjacent nontumorous pancreatic tissues from 102 patients who underwent curative surgery for PanNETs were subjected to immunochemical staining for STK33 and HIF-1α. The relationships among STK33 expression levels, HIF-1α expression levels, clinicopathological parameters and clinical prognoses were statistically analysed. The effects of STK33 on PanNET growth and glycolysis were examined via shRNA-mediated knockdown and overexpression in vitro and in vivo.

Increased STK33 expression in PanNETs correlated significantly with shorter disease-free survival (P < 0.001). STK33 knockdown suppressed cell proliferation, glucose uptake, lactate/ATP production, and S6K1 phosphorylation, whereas STK33 overexpression enhanced these effects. Inhibition of S6K1 (PF-4708671) reversed STK33-driven glycolysis and tumorigenesis. In vivo, STK33 increased tumour growth concurrent with enhanced S6K1 phosphorylation. Mechanistically, HIF-1α transcriptionally upregulated STK33, whereas STK33 promoted increased HIF-1α protein levels via mTORC1/S6K1 signalling, enhancing the expression of the glycolytic enzyme LDHA. Clinically, STK33 and HIF-1α were strongly coexpressed in PanNET tissues (ρ = 0.771; P < 0.001), and both predicted poor prognoses.

Our results support a model in which STK33 functions as a key regulator of the mTORC1/S6K1/HIF-1α signaling-metabolic axis in PanNETs, highlighting its potential as a therapeutic target.