Work

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

Year: 2026

Type: article

Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Source: Journal of Translational Medicine

DOI: 10.1186/s12967-026-08279-8

Authors: Bo Zhou, Canyang Zhan, Zhenzhen Gao, Fei Xiang, Sheng Yan

Institutions: Second Affiliated Hospital of Zhejiang University, Zhejiang University, Children's Hospital of Zhejiang University

Language: English

Topic: Cancer, Hypoxia, and Metabolism

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,890