Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway

Lin, Xiaojing; Fang, Qin; Chen, Shuya; Zhe, Nana; Chai, Qiang; Yu, Meisheng; Zhang, Yaming; Wang, Ziming; Wang, Jishi

doi:10.1016/j.leukres.2015.02.009

Cited by 40 publications

(43 citation statements)

References 36 publications

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“…Moreover, in the majority of AML patients, especially in those with acute monocytic leukemia and leukocytosis, HO-1 is aberrantly overexpressed. In this context, it has been demonstrated that in a mouse xenograft model of AML, HO-1 silencing extends the survival rate [98]. Furthermore, HO-1 protects AML cells from the apoptosis induced by proteasome inhibitor, bortezomib [99], or to front-line chemotherapeutic agents such as cytarabine and daunorubicin and HO-1 downregulation favors apoptosis [100].…”

Section: Ho-1 In Cancer Growth and Resistance To Therapymentioning

confidence: 99%

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation

et al. 2017

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The upregulation of heme oxygenase-1 (HO-1) is one of the most important mechanisms of cell adaptation to stress. Indeed, the redox sensitive transcription factor Nrf2 is the pivotal regulator of HO-1 induction. Through the antioxidant, antiapoptotic, and antinflammatory properties of its metabolic products, HO-1 plays a key role in healthy cells in maintaining redox homeostasis and in preventing carcinogenesis. Nevertheless, several lines of evidence have highlighted the role of HO-1 in cancer progression and its expression correlates with tumor growth, aggressiveness, metastatic and angiogenetic potential, resistance to therapy, tumor escape, and poor prognosis, even though a tumor- and tissue-specific activity has been observed. In this review, we summarize the current literature regarding the pro-tumorigenic role of HO-1 dependent tumor progression as a promising target in anticancer strategy.

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Section: Ho-1 In Cancer Growth and Resistance To Therapymentioning

confidence: 99%

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation

et al. 2017

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“…Our research team had previously proved that overexpression of heme oxygenase-1 (one of Nrf2 target genes) promoted proliferation and increased resistance to Ara-C induced apoptosis of AML cells in vitro and the leukemia's progression of AML in vivo by activating the JNK/c-Jun signaling pathway [50]. The c-Jun oncogene is a member of the activator protein-1 (AP-1) family of transcription factors that is phosphorylated and activated by the JNK [51].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia through inhibiting MSH2

Liu

Wang

et al. 2020

Preprint

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Background: Nuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. Gene mutation is a crucial reason of chemotherapy-resistance in acute myeloid leukemia (AML). However, the relationship between Nrf2 and tumor mutation burden and its mechanism in regulating chemotherapy-resistance remains unclear. Methods: The whole-exome sequencing analysis were used to measure tumor mutation. RNA sequencing, Oncomine, qRT-PCR, Western blotting and immunocytochemistry were employed to detect differences in genes and proteins. The KEGG pathway enrichment analysis and GeneMANIN were performed pathway analysis. Functional assays, such as annexin V/PI, Hoechst33342 staining and DCFH were performed to examine the apoptosis and reactive oxygen species (ROS) of AML cells in vitro. Subcutaneous xenograft model was established to investigate in vivo growth. Results: Nrf2 expression was associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of gene mutant drug resistance in vivo. Furthermore, Nrf2 overexpression inhibited MSH2 protein expression, which caused DNA mismatch repair (MMR) deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells, which inhibited the expression of MSH2 protein. Conclusions: Our findings provided evidence that high Nrf2 expression inhibited MSH2 expression, caused MMR deficiency and increased the tumor mutation burden, which can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.

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“…The protein is proposed to be an important molecular factor promoting the proliferation and anti-apoptosis of leukemic cells [23][24][25]. Ewing et al additionally demonstrated that GVHD in allo-HSCT mice is reduced when HO-1 expression is increased, along with prolonged survival time [26].…”

Section: Discussionmentioning

confidence: 99%

Identification of Heme Oxygenase-1 as a Novel Predictor of Hematopoietic Stem Cell Transplantation Outcomes in Acute Leukemia

Wang

et al. 2016

Cell Physiol Biochem

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Objective: The main aim of this study was to determine the correlation between clinical outcome and heme oxygenase-1 (HO-1) expression before and after hematopoietic stem cell transplantation (HSCT) in acute leukemia. Methods: HO-1 mRNA levels in 83 patients were measured using qRT-PCR. In a comparative analysis of HO-1 levels in relation to different post-transplant outcomes, the HO-1 threshold, determined via the receiver operating characteristic (ROC) curve, was effectively used to predict clinical relapse and acute graft-versus-host disease (aGVHD). The correlations among clinical relapse, aGVHD and HO-1 expression were analyzed based on this threshold. Results: Leukemia risk stratification and relative expression of HO-1 before pretreatment had significant effects on clinical relapse. Leukemia risk stratification, relative expression of HO-1 after HSCT and the interval from diagnosis to transplantation had a significant influence on aGVHD. Both relapse and aGVHD appeared to be associated with relative HO-1 expression. The relative expression rate of HO-1 was 1.131-1.186 before pretreatment, and strongly associated with post-transplantation relapse. The relative expression rate of HO-1 was 1.102-1.144 after transplantation, and closely related to aGVHD. ROC curve analysis revealed high specificity and sensitivity of HO-1 expression in predicting relapse and aGVHD after allo-HSCT. Conclusions: HO-1 expression can be effectively used as a predictor of relapse as well as a diagnostic factor of aGVHD after transplantation for allo-HSCT patients with acute leukemia.

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Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway

Cited by 40 publications

References 36 publications

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia through inhibiting MSH2

Identification of Heme Oxygenase-1 as a Novel Predictor of Hematopoietic Stem Cell Transplantation Outcomes in Acute Leukemia

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