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Mitochondrial Dysfunction Fuels Drug Resistance in Adult T-cell Acute Lymphoblastic Leukemia

ABSTRACT: Following our previous work indicating that a decreased mitochondrial activity is an important feature of tumour aggressiveness in adult T-ALL, we assembled the largest known tumour bank, consisting of 133 samples, to uncover the underlying mechanism. Transcriptomic analysis of these tumours showed that down-regulation of mitochondrial activity plays a central role in mediating the activation of ABCB1, a gene associated with multidrug resistance. Furthermore, our research identified de novo lipid synthesis and lipid accumulation as key mechanisms facilitating ABCB1 activation in T-ALL. Lipid accumulation, together with down-regulation of β-oxidation, promote the activation of lipogenic transcription factors, LXRs, which are the strong drivers of ABCB1 gene activation. This knowledge not only allows us to better understand the biology of aggressive T-ALL, but also to shed light on the mechanisms underlying tumour resistance to induction chemotherapy. We propose that in patients with tumours exhibiting low mitochondrial activity, the inhibition of de novo lipogenesis and restriction of dietary fats, such as caprylic acid, could mitigate the treatment resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280250 | GEO | 2025/05/29

REPOSITORIES: GEO

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Project description:Recent studies have suggested that elevated expression of aldoketoreductase (AKR) 1C1 or 1C2 in tumour cells is associated with increased resistance to DNA damaging agents such as cisplatin and doxorubicin. However, it has not been shown whether selection of tumour cells for resistance to DNA-damaging anthracyclines actually results in increased expression of AKRs and increased conversion of anthracyclines to 10-fold less toxic 13-hydroxy metabolites. It is also unclear whether the induction of aldokeoreductases is temporally correlated with the onset of anthracycline resistance and whether there is a direct relationship between the level of AKR expression or activity and the magnitude of drug resistance. Through microarray profiling of MCF-7 breast cancer cells selected for progressive resistance to doxorubicin or epirubicin, we have identified several genes whose expression has been correlated with both the onset and magnitude of drug resistance, including a “1C” AKR. AKR 1C overexpression was verified by quantitative PCR. Also associated with the onset of anthracycline resistance were genes involved in drug transport (ABCB1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), ROS protection (TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). Consistent with the role of AKRs in anthracycline resistance, doxorubicin- and epirubicin-resistant breast tumour cells exhibited 2.2-fold and 6.1-fold higher levels of the 13-hydroxy metabolite of doxorubicin (doxorubicinol) than wildtype MCF-7 cells. In addition, an inhibitor of AKR 1C2 (5beta-cholanic acid) almost completely restored sensitivity to doxorubicin in Abcb1-deficient doxorubicin-resistant cells, while having no effect on Abcb1-expressing epirubicin-resistant cells. Taken together, our findings strongly suggest the involvement of multiple genes in the acquisition of anthracycline resistance in breast tumor cells---in particular redox genes such as the 1C AKRs. Keywords: Drug resistance of breast cancer cells

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Mitochondrial Dysfunction Fuels Drug Resistance in Adult T-cell Acute Lymphoblastic Leukemia

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