Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

Gampala, Silpa; Shah, Fenil; Zhang, Chi; Rhodes, Steven D.; Babb, Olivia; Grimard, Michelle; Wireman, Randall; Rad, Ellie; Calver, Brian L.; Bai, Ren Yuan; Staedtke, Verena; Hulsey, Emily; Saadatzadeh, M. Reza; Pollok, Karen E.; Tong, Yan; Smith, Abbi E.; Clapp, D. Wade; Tee, Andrew R.; Kelley, Mark R.; Fishel, Melissa L.

doi:10.1038/s41416-021-01270-8

Cited by 13 publications

(19 citation statements)

References 41 publications

(61 reference statements)

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“…Together, our gene expression findings indicate that APE1 coordinates and is involved in most of the steps of BER; alterations in its cellular level impact other important genes in the BER pathway [ 36 ]. This contrasts with what has been observed in cancer studies [ 24 , 37 ].…”

Section: Discussioncontrasting

confidence: 99%

Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

Mijit

Liu

Sishtla

et al. 2023

IJMS

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APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1, APE1 or APEX1; redox factor-1, Ref-1) is a dual-functional enzyme with crucial roles in DNA repair, reduction/oxidation (redox) signaling, and RNA processing and metabolism. The redox function of Ref-1 regulates several transcription factors, such as NF-κB, STAT3, HIF-1α, and others, which have been implicated in multiple human diseases, including ocular angiogenesis, inflammation, and multiple cancers. To better understand how APE1 influences these disease processes, we investigated the effects of APEX1 knockdown (KD) on gene expression in human retinal endothelial cells. This abolishes both DNA repair and redox signaling functions, as well as RNA interactions. Using RNA-seq analysis, we identified the crucial signaling pathways affected following APEX1 KD, with subsequent validation by qRT-PCR. Gene expression data revealed that multiple genes involved in DNA base excision repair, other DNA repair pathways, purine or pyrimidine metabolism signaling, and histidine/one carbon metabolism pathways were downregulated by APEX1 KD. This is in contrast with the alteration of pathways by APEX1 KD in human cancer lines, such as pancreatic ductal adenocarcinoma, lung, HeLa, and malignant peripheral nerve sheath tumors. These results highlight the unique role of APE1/Ref-1 and the clinical therapeutic potential of targeting APE1 and pathways regulated by APE1 in the eye. These findings provide novel avenues for ocular neovascularization treatment.

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Section: Discussioncontrasting

confidence: 99%

Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

Mijit

Liu

Sishtla

et al. 2023

IJMS

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“…APE1/Ref-1′s role in DNA repair, RNA quality control, miRNA metabolism and redox activation of transcription factors NF-κB, HIF-1α, STAT3, AP-1 and p53 has suggested that it may be a therapeutic target for many cancers [ 15 , 17 , 64 ]. Increased expression of APE1/Ref-1 is associated with cancer progression, angiogenesis and resistance to therapy in many cancers, including cancers of the pancreas, bladder, colon, prostate, lung, breast, liver, ovary, bone, malignant peripheral nerve-sheath tumors (MPNST), sarcomas and many more [ 15 , 17 , 26 , 36 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Pharmacologically inhibiting the redox function of APE1/Ref-1 may be beneficial for the treatment of various cancers, as the inhibition of APE1/Ref-1 has been associated with enhanced colorectal cancer tumor regression in preclinical studies and enhanced promyelocytic leukemia response to treatment [ 15 , 38 , 64 ].…”

Section: Targeting Ape1/ref-1 As a Therapeutic Approachmentioning

confidence: 99%

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

Hartman

Lambert-Cheatham

Kelley

et al. 2021

IJMS

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Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.

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“…Inhibitors of DNA repair proteins have widely been studied alone or in conjunction with radiotherapy to enhance tumor suppression. For instance, the inhibition of the DNA base excision repair (BER) protein apurinic/apyrimidinic endonuclease, APE1, has been shown to suppress growth of several cancers ( 33 , 34 ). Similarly, overexpression of APE1 has been linked to radioresistance ( 35 , 36 ), and suppression has been shown to enhance cancer cells to RT ( 37 ).…”

Section: How Does Radiation Work: the Biologic Effects Of Radiationmentioning

confidence: 99%

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

et al. 2021

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In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ‘‘one size fits all’’ paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.

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Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

Cited by 13 publications

References 41 publications

Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

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