Inhibition of c-Myc Overcomes Cytotoxic Drug Resistance in Acute Myeloid Leukemia Cells by Promoting Differentiation

Pan, Xiao Na; Chen, Jia Jie; Wang, Le Xun; Xiao, Ruo Zhi; Liu, Ling Ling; Fang, Zhi Gang; Liu, Quentin; Long, Zi; Dong, Lin

doi:10.1371/journal.pone.0105381

Cited by 73 publications

(70 citation statements)

References 32 publications

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“…c-Myc is aberrantly expressed in a wide variety of human solid tumors as well as leukemia, where its expression is closely related to chemotherapy resistance (Leonetti et al, 1999;Knapp et al, 2003;Delgado et al, 2013). Differentiation is accompanied by downregulation of c-Myc, whose ectopic expression blocks terminal differentiation in various cellular models (Coppola and Cole, 1986;Larsson et al, 1988;GomezCasares et al, 2013), including the ATRA-induced NB4 cell differentiation model used in the present study (Pan et al, 2014). NB4-LR1 SFD cells treated with 10058-F4 combined with ATRA underwent a strong decrease of c-Myc protein.…”

Section: Discussionmentioning

confidence: 76%

“…The induction of C/EBPb is shown as an early critical mediator of ATRA-mediated granulocytic differentiation in APL cells (D'Alo' et al, 2003;Duprez et al, 2003;Truong et al, 2003). Because c-Myc is known to inhibit cell differentiation through C/EBPb (Mink et al, 1996;Duprez et al, 2003;Pan et al, 2014), we wanted to know whether the pharmacological inhibition of c-Myc was sufficient to replace the effect of 8-CPT-cAMP to restore NB4-LR1 SFD cell differentiation and C/EBPb induction by ATRA. For this, we used the 10058-F4 c-Myc inhibitor small molecule.…”

Section: -Cpt-camp Induces the Proteasomal Degradation Of C-myc In Tmentioning

confidence: 99%

“…For this, we used the 10058-F4 c-Myc inhibitor small molecule. Although originally described to disrupt mainly the c-Myc/Max heterodimerization (Follis et al, 2009), this inhibitor decreases cMyc protein level and induces myeloid differentiation in acute myeloid leukemia cells (Huang et al 2006;Lin et al, 2007;Zirath et al, 2013;Pan et al, 2014). These two properties constitute the rational basis for using this compound to investigate the role of c-Myc protein in PKA-mediated differentiation.…”

Section: -Cpt-camp Induces the Proteasomal Degradation Of C-myc In Tmentioning

confidence: 99%

“…c-Myc increases the expression of the hTERT gene coding for the catalytic subunit of telomerase (Oh et al, 1999;Wu et al, 1999), whose activity is required for the unlimited growth potential of tumor cells (Greider, 1999), whereas it downregulates the CCAAT/ enhancer binding protein b (C/EBPb) transcription factor that promotes the differentiation of numerous cell types, including the final maturation of acute promyelocytic leukemia (APL) cells (Mink et al, 1996;Duprez et al, 2003;Pan et al, 2014). Because of its role in multiple cellular pathways, a tight control of c-Myc level is required.…”

Section: Introductionmentioning

confidence: 99%

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cAMP-Dependent Protein Kinase A (PKA)–Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes

Nguyen

Døskeland

et al. 2015

Mol Pharmacol

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The transcription factor c-Myc regulates numerous target genes that are important for multiple cellular processes such as cell growth and differentiation. It is commonly deregulated in leukemia. Acute promyelocytic leukemia (APL) is characterized by a blockade of granulocytic differentiation at the promyelocyte stage. Despite the great success of all-trans retinoic acid (ATRA)-based therapy, which results in a clinical remission by inducing promyelocyte maturation, a significant number of patients relapse due to the development of ATRA resistance. A significant role has been ascribed to the cAMP/cAMP-dependent protein kinase A (PKA) signaling pathway in retinoid treatment since PKA activation is able to restore differentiation in some ATRA-resistant cells and eradicate leukemia-initiating cells in vivo. In this study, using NB4 APL cell variants resistant to ATRA-induced differentiation, we reveal distinct functional roles of the two PKA isozymes, PKA type I (PKA-I) and PKA-type II (PKA-II), on the steady-state level of c-Myc protein, providing a likely mechanism by which cAMP-elevating agents can restore differentiation in ATRA maturation-resistant APL cells. Therefore, both the inhibition of c-Myc activity and the PKA-I/PKA-II ratio should be taken into account if cAMP-based therapy is considered in the clinical management of APL.

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Section: Discussionmentioning

confidence: 76%

Section: -Cpt-camp Induces the Proteasomal Degradation Of C-myc In Tmentioning

confidence: 99%

Section: -Cpt-camp Induces the Proteasomal Degradation Of C-myc In Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

cAMP-Dependent Protein Kinase A (PKA)–Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes

Nguyen

Døskeland

et al. 2015

Mol Pharmacol

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“…70,71 MYC overexpression in AML induced resistance to chemotherapeutic drugs. 72 Increased MYC levels were correlated with decreased microRNA-29 family expression in AML. 73 …”

Section: Acute Myeloid Leukemiamentioning

confidence: 98%

MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

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Transcriptional upregulation of c‐MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma

2018

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AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c‐MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c‐MYC markedly sensitizes AXL‐dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c‐MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c‐MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c‐MYC expression through activation of the AKT/β‐catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c‐MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin‐resistant tumors with overexpression of AXL and activation of c‐MYC.

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Inhibition of c-Myc Overcomes Cytotoxic Drug Resistance in Acute Myeloid Leukemia Cells by Promoting Differentiation

Cited by 73 publications

References 32 publications

cAMP-Dependent Protein Kinase A (PKA)–Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes

cAMP-Dependent Protein Kinase A (PKA)–Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes

MYC as therapeutic target in leukemia and lymphoma

Transcriptional upregulation of c‐MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma

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