Metabolic characterization of imatinib-resistant BCR-ABL T315I chronic myeloid leukemia cells indicates down-regulation of glycolytic pathway and low ROS production

Ko, Byung Woong; Han, Jeongsu; Heo, Jun Young; Jang, Yunseon; Kim, Soo Jeong; Kim, Jungim; Lee, Min Joung; Ryu, Min Jeong; Song, Ik Chan; Jo, Young Suk; Kweon, Gi Ryang

doi:10.3109/10428194.2016.1142086

Cited by 13 publications

(15 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…During OXPHOS, reactive oxygen species (ROS) are generated by mitochondria [17]. We found decreased intracellular ROS levels in both resistant cell lines as compared to their sensitive parental cells ( Figure S5), which is concordant with a low ROS production in imatinib-resistant chronic myeloid leukemia cell lines [18].…”

Section: Heterogeneity Of Energy Metabolism Among Imatinib-resistant supporting

confidence: 66%

Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor

Huang

Gao

Chen

et al. 2020

Cells

View full text Add to dashboard Cite

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.

show abstract

Section: Heterogeneity Of Energy Metabolism Among Imatinib-resistant supporting

confidence: 66%

Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor

Huang

Gao

Chen

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Previous research has shown that GPx1 is an effective antioxidant enzyme that cannot be replaced by any other selenoprotein to protect against generalized oxidative stress [74][75][76]. When cancerous cells are generated, the expression of GPx1 is abnormal, causing intracellular ROS dysfunction [77,78]. Due to its antioxidant properties, GPx1 is thought to be highly effective in preventing the ROS-mediated initiation of cancer.…”

Section: Gpx1mentioning

confidence: 99%

Involvement of glutathione peroxidases in the occurrence and development of breast cancers

Zhang

Chen

et al. 2020

J Transl Med

View full text Add to dashboard Cite

Glutathione peroxidases (GPxs) belong to a family of enzymes that is important in organisms; these enzymes promote hydrogen peroxide metabolism and protect cell membrane structure and function from oxidative damage. Based on the establishment and development of the theory of the pathological roles of free radicals, the role of GPxs has gradually attracted researchers' attention, and the involvement of GPxs in the occurrence and development of malignant tumors has been shown. On the other hand, the incidence of breast cancer in increasing, and breast cancer has become the leading cause of cancer-related death in females worldwide; breast cancer is thought to be related to the increased production of reactive oxygen species, indicating the involvement of GPxs in these processes. Therefore, this article focused on the molecular mechanism and function of GPxs in the occurrence and development of breast cancer to understand their role in breast cancer and to provide a new theoretical basis for the treatment of breast cancer.

show abstract

“…Selected recent research indicates that cells resistant to IM demonstrate lower levels of expression of ROS scavengers such as GPx and catalase [40]. Interestingly, we observed that after exposure to IM the GPx and catalase activity increased in IM-resistant CML cells in comparison to IM-susceptible cells.…”

Section: Discussionmentioning

confidence: 46%

“…On the other hand, it has been recently demonstrated that CML cells resistant to IM through T315I mutation exhibit a lower level of ROS production when compared to CML cells susceptible to IM action. However, those results were gathered using a different cell lines than the ones used by us, which might serve as an explanation for the observed differences [40].…”

Section: Discussionmentioning

confidence: 87%

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

et al. 2021

View full text Add to dashboard Cite

Chronic myeloid leukemia (CML) develops due to the presence of the BCR-ABL1 protein, a target of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), used in a CML therapy. CML eradication is a challenge due to developing resistance to TKIs. BCR-ABL1 induces endogenous oxidative stress leading to genomic instability and development of TKI resistance. Model CML cells susceptible or resistant to IM, as well as wild-type, non-cancer cells without the BCR-ABL1 protein were treated with IM, hydrogen peroxide (H2O2) as a model trigger of external oxidative stress, or with IM+H2O2. Accumulation of reactive oxygen species (ROS), DNA damage, activity of selected antioxidant enzymes and glutathione (GSH), and mitochondrial potential (MMP) were assessed. We observed increase in ROS accumulation in BCR-ABL1 positive cells and distinct levels of ROS accumulation in IM-susceptible cells when compared to IM-resistant ones, as well as increased DNA damage caused by IM action in sensitive cells. Depletion of GSH levels and a decreased activity of glutathione peroxidase (GPx) in the presence of IM was higher in the cells susceptible to IM. IM-resistant cells showed an increase of catalase activity and a depletion of MMP. BCR-ABL1 kinase alters ROS metabolism, and IM resistance is accompanied by the changes in activity of GPx, catalase, and alterations in MMP.

show abstract

Metabolic characterization of imatinib-resistant BCR-ABL T315I chronic myeloid leukemia cells indicates down-regulation of glycolytic pathway and low ROS production

Cited by 13 publications

References 27 publications

Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor

Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor

Involvement of glutathione peroxidases in the occurrence and development of breast cancers

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

Contact Info

Product

Resources

About