Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor

Abstract

Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.

Postdiagnostic metformin use and survival of patients with colorectal cancer: A Nationwide cohort study

“…Our study further characterized the bioenergetic profile in imatinib-resistant GIST cells. We found that imatinib-resistant GIST cells can harbor high metabolic status (upregulated high glycolysis and OXPHOS status) and low OXPHOS status, suggesting the heterogeneity of metabolic reprogramming in GIST cells surviving imatinib cytotoxicity [169].…”

Melatonin Targets Metabolism in Head and Neck Cancer Cells by Regulating Mitochondrial Structure and Function

“…Our findings indicate that glycolysis inhibition and increased OXPHOS activity could explain, at least partially, the inhibition of metabolic reprogramming by melatonin in HNSCC cells. OXPHOS deficiency also closely correlates with the invasive and metastatic properties of tumor cells [ 38 ]. Our results conclude that melatonin treatment increases TCA intermediates such as acetyl-CoA, citric acid, and succinyl-CoA, as well as NADH, but decreases pyruvate levels.…”

“…Glycolysis is generally used by cancer cells for ATP production rather than mitochondrial respiration, even in the presence of adequate oxygen [ 37 ]. In addition, resistant cells can acquire a glycolytic metabolism to survive cytotoxic stress [ 38 ]. Given that glycolytic marker expression in HNSCC is associated with poor survival rates and resistance to chemo and radiotherapy [ 2 ], we observed that melatonin decreases glycolysis.…”

“…Given that glycolytic marker expression in HNSCC is associated with poor survival rates and resistance to chemo and radiotherapy [ 2 ], we observed that melatonin decreases glycolysis. On the whole, these findings indicate that glycolysis inhibition and increased OXPHOS might explain, at least partly, the inhibition of metabolic reprogramming induced by melatonin in HNSCC cells [ 38 ].…”

Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors

“…The underlying mechanism of metabolic reprogramming upon imatinib treatment in GIST remains elusive. We previously demonstrated that imatinib also suppressed mitochondrial biogenesis [ 11 ], suggesting that imatinib does not induce OXPHOS through mitochondrial biogenesis. In the present study, we speculate that imatinib might induce OXPHOS through microRNA regulation in GIST.…”