A stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemia

Williams, Mark S.; Amaral, Fabio; Simeoni, Fabrizio; Somervaille, Tim C. P.

doi:10.1172/jci130809

Cited by 28 publications

(29 citation statements)

References 54 publications

(62 reference statements)

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“…Aberrant expression of the ATP-binding cassette (ABC) transport family is a vital mechanism causing chemotherapy resistance in multiple tumors. ATF4 induces drug resistance in acute myeloid leukemia (AML) by binding to the ABCB1 promoter 25 . To investigate the role of the ABC transport family in ATF4-centered gemcitabine resistance in pancreatic cancer, we analyzed the relationship between ATF4 mRNA expression and ABC transport family mRNA expression in the gene expression profiling interactive analysis website with TCGA and GTEx datasets.…”

Section: Resultsmentioning

confidence: 99%

Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation

Wei

et al. 2021

Cell Death Dis

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Cancer-associated fibroblasts (CAFs) contribute to malignant progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, little is known about the underlying mechanism. In this study, we investigated the potential role and mechanisms of activating transcription factor 4 (ATF4) in CAFs-induced malignancy and gemcitabine resistance. We demonstrated that ATF4 is overexpressed in PDAC and associated with a poor prognosis. Silencing ATF4 expression decreased proliferation, colony formation, migration, gemcitabine sensitivity, and sphere formation. Subsequently, we revealed that CAFs secrete TGF-β1 to upregulate the expression of ATF4 in PDAC cells via the SMAD2/3 pathway and induce cancer progression, cancer stemness, and gemcitabine resistance. Furthermore, we demonstrated that ATF4 directly binds to the ABCC1 promoter region to activate transcription. In summary, these data demonstrate that CAFs contribute to malignancy and gemcitabine resistance in PDAC by upregulating the expression of ATF4 via the TGF-β1/SMAD2/3 axis and highlight that ATF4 is an attractive therapeutic target for combating gemcitabine resistance in PDAC.

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Section: Resultsmentioning

confidence: 99%

Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation

Wei

et al. 2021

Cell Death Dis

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“…Parenterally administered ISRIB has been shown to inhibit eIF2a phosphorylation with an IC50 of 5 nM, and when given to mice it achieves its Cmax at 2h and has a T1/2 of 8h (60). In cell-based studies it has shown typical direct dose response relationships (60)(61)(62). Animal studies characterizing its efficacy for memory or traumatic brain injury have typically used doses of 2.5 mg/kg, and these evaluations have also shown direct dose response relationships (60,63).…”

Section: Discussionmentioning

confidence: 99%

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

Bhattacharya¹,

Xiao²,

Chatterjee³

et al. 2021

Journal of Clinical Investigation

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“…Apart from the well-documented undesirable impact of SGs, researchers have identified other aspects of the ISR that negatively impact cancer prognosis and treatment. In acute myeloid leukemia patients, repeat exposure to daunorubicin has been shown to induce the ISR and ATF4 expression, resulting in increased drug efflux, via ATP binding cassette subfamily B member 1 (ABCB1), and treatment failure [ 121 ]. When ISRIB and U0126, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor, were used to inhibit stress signaling, daunorubicin-resistant K562 bone marrow cells were resensitized to drug [ 121 ].…”

Section: Mammalian Orthoreovirus Modulation Of the Isr Impact On Cmentioning

confidence: 99%

“…In acute myeloid leukemia patients, repeat exposure to daunorubicin has been shown to induce the ISR and ATF4 expression, resulting in increased drug efflux, via ATP binding cassette subfamily B member 1 (ABCB1), and treatment failure [ 121 ]. When ISRIB and U0126, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor, were used to inhibit stress signaling, daunorubicin-resistant K562 bone marrow cells were resensitized to drug [ 121 ]. In addition, gemcitabine-resistant pancreatic ductal adenocarcinoma has increased gemcitabine-mediated apoptosis when ISRIB or siRNA against ATF4 is introduced to cells [ 20 ].…”

Section: Mammalian Orthoreovirus Modulation Of the Isr Impact On Cmentioning

confidence: 99%

Reovirus and the Host Integrated Stress Response: On the Frontlines of the Battle to Survive

Bussiere¹,

Miller²

2021

Viruses

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Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I–III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.

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A stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemia

Cited by 28 publications

References 54 publications

Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation

Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

Reovirus and the Host Integrated Stress Response: On the Frontlines of the Battle to Survive

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