Kumar, Poulami (2024) Targeting Unique Metabolic Signatures in Gastrointestinal Cancers with Selective Full Agonists of Cannabinoid Receptors. [Tesi di dottorato]

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Abstract

External stimuli significantly influence the gastrointestinal (GI) tract and employ various metabolic pathways to maintain physiological homeostasis. Consequently, gastric and colon cancers, shaped by their differing tissue environments, genetic profiles, and biological behaviors, exhibit unique metabolic characteristics that result in distinct metabolomic signatures, affecting their growth, spread, and responses to treatment. Reprogrammed metabolism and rewiring metabolic networks are widely recognized hallmarks of oncogenic progression, and targeting these alterations is increasingly considered a therapeutic strategy to enhance current chemotherapy and immunotherapy approaches. Cannabinoids have garnered attention for their potential antitumor properties in various cancers, including gastric and colon cancer. Research on the effects of cannabinoids in these contexts has highlighted their therapeutic role in inhibiting tumor growth and viability through both cannabinoid receptor-mediated and non-cannabinoid receptor-mediated mechanisms. However, a comprehensive study investigating the effects of cannabinoids on the metabolism of gastric and colon cancers has yet to be conducted. The study began with the profilation of the metabolomes of various gastric (AGS and MKN45) and colon (HCT116 and HT29) cancer cells. NMR-based OPLS-DA was applied to distinguish the metabolic profiles between gastric and colon cancer cells. The model exhibited a significant class separation, indicating that these two types of cancer rely on a distinct array of metabolites to meet their high energy demands. When we examined the effect of two cannabinoids (ACEA, as a selective CB1 full agonist, and JWH133 as a selective CB2 full agonist) on the main metabolic pathways in AGS and HCT116 cells, we noted differences in how the two cancer cells responded metabolically to the treatments. In general, we observed mirrored modulation depending on the type of cancer. Specifically, both cannabinoids down-regulated maximal respiratory capacity and complex IV activity, as well as aspartate-glutamate metabolism, in gastric cancer cells (AGS), while promoting the maximal respiratory capacity and complex IV activity and up-regulating the alanine-glutamate pathways in colon cancer cells (HCT116). A similar trend was observed regarding the glycolytic capacity. In HCT116 cells, both treatments significantly diminished the extracellular acidification rate (ECAR), while ACEA and particularly JWH133 increased ECAR in AGS cells. Additional opposing effects upon treatments in AGS and HCT116 cells were observed on the mRNA expression of the mitochondrial isoform enzyme regulating the glucose-alanine cycle GPT1 and the serine-glutamine transporter ASCT2. Notably, ACEA and JWH133 reduced cell growth – although with a different extent – migration, and stemness marker gene expression, irrespective of the cancer type. Finally, there was a difference in how treatments impacted homotypic tumor spheroid formation. In AGS and HCT116 cells, JWH133 strongly impacted both the size and the number of spheroids, while ACEA was able to reduce spheroids diameter only in HCT116 cells. The results suggest that cannabinoids can interfere with the distinct metabolic strategies used by GI tumors to evade control over cell fate. Further analyses are needed to address the therapeutic potential of these molecules as specific metabolic inhibitors for GI cancer therapy.

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