The Leloir Cycle in Glioblastoma: Galactose Scavenging and Metabolic Remodeling

Abstract

Background: Glioblastoma (GBM) can use metabolic fuels other than glucose (Glc). The ability of GBM to use galactose (Gal) as a fuel via the Leloir pathway is investigated. Methods: Gene transcript data were accessed to determine the association between expression of genes of the Leloir pathway and patient outcomes. Growth studies were performed on five primary patient-derived GBM cultures using Glc-free media supplemented with Gal. The role of Glut3/Glut14 in sugar import was investigated using antibody inhibition of hexose transport. A specific inhibitor of GALK1 (Cpd36) was used to inhibit Gal catabolism. Gal metabolism was examined using proton, carbon and phosphorous NMR spectroscopy, with 13C-labeled Glc and Gal as tracers. Results: Data analysis from published databases revealed that elevated levels of mRNA transcripts of SLC2A3 (Glut3), SLC2A14 (Glut14) and key Leloir pathway enzymes correlate with poor patient outcomes. GBM cultures proliferated when grown solely on Gal in Glc-free media and switching Glc-grown GBM cells into Gal-enriched/Glc-free media produced elevated levels of Glut3 and/or Glut14 enzymes. The 13C NMR-based metabolic flux analysis demonstrated a fully functional Leloir pathway and elevated pentose phosphate pathway activity for efficient Gal metabolism in GBM cells. Conclusion: Expression of Glut3 and/or Glut14 together with the enzymes of the Leloir pathway allows GBM to transport and metabolize Gal at physiological glucose concentrations, providing GBM cells with an alternate energy source. The presence of this pathway in GBM and its selective targeting may provide new treatment strategies.

Rotating Magnetic Fields Inhibit Mitochondrial Respiration, Promote Oxidative Stress and Produce Loss of Mitochondrial Integrity in Cancer Cells

“…Peak areas of various 13 C signals were determined by deconvolution using the ACD software (Advanced Chemistry Development, Toronto, Canada). 13 C NMR isotopomer analysis was performed as reported in our earlier publications (24,25).…”

Comparing 2 crystal structures and 12 AlphaFold2-predicted human membrane glucose transporters and their water-soluble glutamine, threonine and tyrosine variants

“…For example, overexpression or upregulation of GLUT1, GLUT3, GLUT5 and GLUT12 is widely found in many types of cancers including breast, bladder, cervical, colon, colorectal, oesophageal, glioblastoma, gastric, head and neck, laryngeal, liver, lung, lymphoma, oral squamous cell, ovarian, pancreas, pancreatic islets, penile, prostate, clear renal cell, testis, thyroid, uterine cancers as well as from breast cancer to brain metastasis (Nishioka et al, 1992;Brown and Wahl, 1993;Mellanen et al, 1994;Zamora-Leon et al, 1996;Higashi et al, 1997;Younes et al, 1997;Noguchi et al, 1999;Pedersen et al, 2001;Rogers et al, 2003; Ayala (Schlößer et al, 2017;Du et al, 2020). GLUT 13 (Du et al, 2020) and GLUT14 (Berlth et al, 2015;Valli et al, 2019;Sharpe et al, 2021). 3).…”

“…Overexpression of GLUT2 is found in cancers of the breast, colon, liver, pancreas and small intestine (Tomita, 1999;Godoy et al, 2006;Hamann et al, 2018). Overexpression of GLUT4 is found in breast, gastric, and myeloma, muscle (McBrayer et al, 2012;Guo et al 2021); overexpression of GLUT6 is found in gastric and endometrial cancer and testis (Byrne et al, 2014;Schlößer et al, 2017;Caruana and Byrne, 2020); overexpression of GLUT7 is found in benign prostate cancer (Reinicke et al, 2012); overexpression of GLUT8 is found in myeloma (McBrayer et al, 2012); overexpression of GLUT9 is found in adrenal, heart, kidney, liver, both benign and cancerous prostate (Godoy et al, 2006); overexpression of GLUT11 is found in multiple myeloma and prostate (McBrayer et al, 2012) and overexpression of GLUT14 is found in colon and glioblastoma (Valli et al, 2019;Sharpe et al, 2021). On the other hand, overexpression of GLUT10, GLUT12 and GLUT13 have also been found to be associated with better outcomes in lung adenocarcinoma (Du et al, 2020).…”

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

“…We postulated that primary brain cancers, such as GBM, may initiate Treg infiltration by expressing sperm/testicular proteins, such as Glut14, which we have recently demonstrated in GBM primary cultures and in the GBM transcriptome database [68]. If a GBM were to present a sperm/testicular epitope to a reproductive RORC-Treg, then it would begin Treg infiltration and produce an immunosuppressive micro-environment.…”