HSP90 co-regulates the formation and nuclear distribution of the glycolytic output complex to promote resistance and poor prognosis in gastric cancer patients

Background: Resistance to treatment is a critical factor contributing to poor prognosis in gastric Cancer patients. HSP90 has emerged as a promising therapeutic target; however, its role in regulating tumor metabolic pathways, particularly glycolysis, remains poorly understood, which limits its clinical application.

Methods: We identified proteins that directly interact with HSP90 using immunoprecipitation (IP) followed by mass spectrometry. The relationship between HSP90 and glycolysis was further investigated through transcriptomic analyses and in vitro experiments. Mechanistic insights were obtained through mass spectrometry, co-immunoprecipitation (Co-IP) assays, drug sensitivity tests, and bioinformatics analyses. Additionally, we developed a scoring system based on transcriptomic data to evaluate its prognostic significance and association with treatment resistance in gastric Cancer patients.

Results: Our multi-omics and in vitro studies revealed that HSP90 regulates glycolysis and influences the stemness properties of gastric Cancer cells. Mechanistically, HSP90 facilitates the assembly of a glycolytic multi-enzyme complex, termed the HGEO complex, which enhances glycolytic metabolism. Mechanistically, HSP90 facilitates the formation of a multienzyme complex comprising key Enzymes including PGK1, PKM2, ENO1, and LDHA, thereby facilitating the production of the final glycolytic products. We refer to this as the "HSP90-Glycolytic Output Complex" (HGEO Complex). We quantified this phenomenon with a scoring system (HGScore), finding that patients with a high HGScore exhibited more malignant signatures, increased resistance to treatment, and poorer prognoses. Furthermore, we demonstrated that the HGEO complex is localized in the nucleus, regulated by the nuclear lamina protein LMNA, which further contributes to treatment resistance and adverse outcomes. In vitro experiments indicated that inhibiting the formation of this complex sensitizes gastric Cancer cells to chemotherapy.

Conclusion: Our findings suggest that HSP90 and LMNA mediated the formation and nuclear localization of the HGEO complex, thereby enhancing the malignant traits and resistance mechanisms in gastric Cancer. Targeting this pathway may offer a novel therapeutic strategy to improve treatment outcomes.

Glycolytic multi-enzyme complex; HSP90; LMNA; Nuclear distribution; Tumor resistance.