Neurotherapeutic implications of sense and respond strategies generated by astrocytes and astrocytic tumours to combat pH mechanical stress

Abstract

Aims Astrocytes adapt to acute acid stress. Intriguingly, cancer cells with astrocytic differentiation thrive even better in an acidic microenvironment. How changes in extracellular pH (pHe) are sensed and measured by the cell surface assemblies that first intercept the acid stress, and how this information is relayed downstream for an appropriate survival response remains largely uncharacterized. Methods In vitro cell‐based studies were combined with an in vivo animal model to delineate the machinery involved in pH microenvironment sensing and generation of mechanoadaptive responses in normal and neoplastic astrocytes. The data was further validated on patient samples from acidosis driven ischaemia and astrocytic tumour tissues. Results We demonstrate that low pHe is perceived and interpreted by cells as mechanical stress. GM3 acts as a lipid‐based pH sensor, and in low pHe, its highly protonated state generates plasma membrane deformation stress which activates the IRE1‐sXBP1‐SREBP2‐ACSS2 response axis for cholesterol biosynthesis and surface trafficking. Enhanced surface cholesterol provides mechanical tenacity and prevents acid‐mediated membrane hydrolysis, which would otherwise result in cell leakage and death. Conclusions In summary, activating these lipids or the associated downstream machinery in acidosis‐related neurodegeneration may prevent disease progression, while specifically suppressing this key mechanical ‘sense‐respond’ axis should effectively target astrocytic tumour growth.

Understanding the Combined Effects of High Glucose Induced Hyper-Osmotic Stress and Oxygen Tension in the Progression of Tumourigenesis: From Mechanism to Anti-Cancer Therapeutics

“…Cancer cells were maintained in DMEM (Gibco-12100-046) with 10% Foetal Bovine Serum (Himedia—RM9955) and 1x antibiotics (Himedia—A002). Normal cells were cultured as described previously [ 12 , 13 , 34 ]. All common chemicals were purchased from Sigma-Aldrich, St.Louis, MO unless otherwise indicated.…”

“…In 96-wellround-bottom plates, 3 × 10 4 cells were seeded per well in MEM media [ 12 ]. The plates were centrifuged in a swinging bucket rotor at 500× g for 5 min to generate the 3D cell pellet.…”

“…Tumour cells display robust adaptation to the microenvironment (TME)-associated biomechanical challenges. Therefore, therapeutic targeting of TME-associated mechanoadaptation is emerging as a ‘hot spot’ of tumour cell vulnerability and a promising avenue in cancer eradication [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. High glucose (HG) is not only a hallmark of cancer but also acts as a hyper-osmotic stressor in TME.…”

Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities

“…Fukamachi et al found that reducing GGPP synthesis can inhibit the proliferation of synovial sarcoma cells in acidic environments 168 . Additionally, John et al found that activation of the IRE1-sXBP1-SREBP2-ACSS2 response axis at low pH e promotes cholesterol biosynthesis and cell membrane surface trafficking in astrocytic tumors, thereby enhancing cell membrane surface mechanical tenacity, preventing acid-mediated cell membrane hydrolysis, and supporting tumor cell survival 169 . In addition, Corbet et al found that acidosis-induced TGF-β2 activation facilitated LD accumulation, enhancing the distant metastatic potential of cancer cells 170 .…”