High glucose (HG), a hallmark of the tumour microenvironment, is also a biomechanical stressor, as it exerts hyper-osmotic stress (HG-HO), but not much is known regarding how tumour cells mechanoadapt to HG-HO. Therefore, this study aimed to delineate the novel molecular mechanisms by which tumour cells mechanoadapt to HG/HG-HO and whether phytochemical-based interference in these mechanisms can generate tumour-cell-selective vulnerability to cell death. Mannitol and L-glucose were used as hyper-osmotic equivalents of high glucose. The results revealed that the tumour cells can efficiently mechanoadapt to HG-HO only in the normoxic microenvironment. Under normoxic HG/HG-HO stress, tumour cells polySUMOylate a higher pool of mitotic driver pH3(Ser10), which translocates to the nucleus and promotes faster cell divisions. On the contrary, acute hypoxia dampens HG/HG-HO-associated excessive proliferation by upregulating sentrin protease SENP7. SENP7 promotes abnormal SUMOylation of pH3(Ser10), thereby restricting its nuclear entry and promoting the M-phase arrest and cell loss. However, the hypoxia-arrested cells that managed to survive showed relapse upon reversal to normoxia as well as upregulation of pro-survival-associated SENP1, and players in tumour growth signalling, autophagy, glycolytic pathways etc. Depletion of SENP1 in both normoxia and hypoxia caused significant loss of tumour cells vs undepleted controls. SENP1 was ascertained to restrict the abnormal SUMOylation of pH3(Ser10) in both normoxia and hypoxia, although not so efficiently in hypoxia, due to the opposing activity of SENP7. Co-treatment with Momordin Ic (MC), a natural SENP1 inhibitor, and Gallic Acid (GA), an inhibitor of identified major pro-tumourigenic signalling (both enriched in Momordica charantia), eliminated surviving tumour cells in normal glucose, HG and HG-HO normoxic and hypoxic microenvironments, suggesting that appropriate and enhanced polySUMOylation of pH3(Ser10) in response to HG/HG-HO stress was attenuated by this treatment along with further dampening of other key tumourigenic signalling, due to which tumour cells could no longer proliferate and grow.

Background Glioblastoma multiforme (GBM) is a deadly brain tumour with minimal survival rates due to the ever-expanding heterogeneity, chemo and radioresistance. Kinases are known to crucially drive GBM pathology; however, a rationale therapeutic combination that can simultaneously inhibit multiple kinases has not yet emerged successfully. Results Here, we analyzed the GBM patient data from several publicly available repositories and deduced hub GBM kinases, most of which were identified to be SUMOylated by SUMO2/3 isoforms. Not only the hub kinases but a significant proportion of GBM upregulated genes involved in proliferation, metastasis, invasion, epithelial-mesenchymal transition, stemness, DNA repair, stromal and macrophages maintenance were also identified to be the targets of SUMO2 isoform. Correlatively, high expression of SUMO2 isoform was found to be significantly associated with poor patient survival. Conclusions Although many natural products and drugs are evidenced to target general SUMOylation, however, our meta-analysis strongly calls for the need to design SUMO2/3 or even better SUMO2 specific inhibitors and also explore the SUMO2 transcription inhibitors for universally potential, physiologically non-toxic anti-GBM drug therapy. Graphical Abstract