AKR1C enzymes sustain therapy resistance in paediatric T-ALL

Bortolozzi, Roberta; Bresolin, Silvia; Rampazzo, Elena; Paganin, Maddalena; Maule, Francesca; Mariotto, Elena; Boso, Daniele; Minuzzo, Sonia; Agnusdei, Valentina; Viola, Giampietro; Kronnie, Geertruy te; Cazzaniga, Giovanni; Basso, Giuseppe; Persano, Luca

doi:10.1038/s41416-018-0014-0

Cited by 34 publications

(43 citation statements)

References 42 publications

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“…Interestingly, high levels of AKR1C1 have been implicated in the chemo‐resistance of leukaemia cells (Matsunaga et al , ; Bortolozzi et al , ). Therefore, we analyzed the effect of AKR1C1 expression on the overall survival of AML patients from The Cancer Genomic Atlas (TCGA) database and detected significantly worse survival of the AKR1C1 high‐expressing group (Figure S1B).…”

Section: Discussionmentioning

confidence: 99%

“…Since MSC differentiation is associated with its functions (Chen et al , ), we analyzed the gene expression profiles of the abnormally differentiating AML‐MSCs and identified the human aldo‐keto reductase gene AKR1C1 , which is upregulated in lung cancer, bladder cancer, gastric cancer, leukaemia, etc. (Chang et al , ; Matsunaga et al , ; Matsumoto et al , ; Bortolozzi et al , ; Zhu et al , ). The role of AKR1C1 in the pro‐leukaemic effects of MSCs and the underlying mechanisms were further investigated.…”

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confidence: 99%

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Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

et al. 2020

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The leukaemic bone marrow microenvironment, comprising abnormal mesenchymal stromal cells (MSCs), is responsible for the poor prognosis of acute myeloid leukaemia (AML). Therefore, it is essential to determine the mechanisms underlying the supportive role of MSCs in the survival of leukaemia cells. Through in silico analyses, we identified a total of 271 aberrantly expressed genes in the MSCs derived from acute myeloid leukemia (AML) patients that were associated with adipogenic differentiation, of which aldo-keto reductase 1C1 (AKR1C1) was significantly upregulated in the AML-MSCs. Knockdown of AKR1C1 in the MSCs suppressed adipogenesis and promoted osteogenesis, and inhibited the growth of co-cultured AML cell lines compared to the situation in wild-type AML-derived MSCs. Introduction of recombinant human AKR1C1 in the MSCs partially alleviated the effects of AKR1C1 knockdown. In addition, the absence of AKR1C1 reduced secretion of cytokines such as MCP-1, IL-6 and G-CSF from the MSCs, along with inactivation of STAT3 and ERK1/2 in the cocultured AML cells. AKR1C1 is an essential factor driving the adipogenic differentiation of leukaemic MSCs and mediates its pro-survival effects on AML cells by promoting cytokine secretion and activating the downstream pathways in the AML cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

et al. 2020

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“…Alternatively, the production of reactive oxygen species can cause direct membrane damage of organelles, directly releasing AIF and cytochrome C into the cytosol. New signaling pathways involving NFE2L2 [135][136][137] (aka NRF2) and AKR1C [138] have also been implicated in modulation of and resistance to ROS/redox-mediated cell death. Additionally, the "extrinsic" pathway can be triggered to induce apoptosis; external ligands, such TRAIL, TNFA, or FASL can bind their respective receptors, which then can directly activate CASP8 to trigger apoptosis.…”

Section: Apoptosis Via Cytochrome C Redox/ros Activation and Caspasmentioning

confidence: 99%

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Shah¹

2019

CDR

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While advances in the treatment of pediatric cancers have improved survival to > 80% across all tumor types, drug resistance continues to limit survival for a considerable number of patients. We review the known mechanisms of resistance in pediatric cancers, including processes that impair conventional chemotherapies, newer classes of targeted small molecule antineoplastic drugs, and monoclonal antibodies. We highlight similarities and differences in treatment approach and resistance between pediatric and adult cancers. We also discuss newer areas of research into drug resistance, including extracellular and immune factors.

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“…11,12 It has been discovered pivotal in the development of urogenital, 11,13,14 gastrointestinal [15][16][17][18][19][20][21][22] cancers and more. [23][24][25][26][27] However, previous findings on the exact significance of AKR1C2 have been inconsistent and highly debatable, we even don't know whether to regard it as a promoter or suppresser of cancers, and how it participates in the pathogenesis and development of ESCC have not been fully investigated.…”

Section: Introductionmentioning

confidence: 99%

AKR1C2 acts as a targetable oncogene in esophageal squamous cell carcinoma via activating PI3K/AKT signaling pathway

Zhang

Huang

Zhang

et al. 2020

J Cellular Molecular Medi

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The aldo‐keto reductases family 1 member C2 (AKR1C2) has critical roles in the tumorigenesis and progression of malignant tumours. However, it was also discovered to have ambiguous functions in multiple cancers and till present, its clinical significance and molecular mechanism in oesophageal squamous cell carcinoma (ESCC) has been unclear. The aim of this study was to explore the role of AKR1C2 in the tumorigenesis of ESCC. Here, we showed that AKR1C2 expression was found to be up‐regulated in ESCC tissues and was significantly associated with pathological stage, lymph node metastasis and worse outcomes. Functional assays demonstrated that an ectopic expression of AKR1C2 in ESCC cells resulted in increased proliferation, migration and cisplatin resistance, while knockdown led to inversing effects. Bioinformation analyses and mechanistic studies demonstrated that AKR1C2 activated the PI3K/AKT signalling pathway, furthermore, the inhibitor of PI3K or the selective inhibitor of AKR1C2 enzyme activity could reverse the aggressiveness and showed synergistic antitumour effect when combined with cisplatin, both in vitro and in vivo. In conclusion, Our findings revealed that AKR1C2 could function as an oncogene by activating the PI3K/AKT pathway, as a novel prognostic biomarker and/or as a potential therapeutic target to ESCC.

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AKR1C enzymes sustain therapy resistance in paediatric T-ALL

Abstract: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.

Cited by 34 publications

References 42 publications

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

AKR1C2 acts as a targetable oncogene in esophageal squamous cell carcinoma via activating PI3K/AKT signaling pathway

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