MUC1-C Oncoprotein Interacts Directly with ATM and Promotes the DNA Damage Response to Ionizing Radiation

Huang, Lei; Liao, Xiaodong; Beckett, Michael A.; Li, Yuan; Khanna, Kum Kum; Wang, Zhugang; Kharbanda, Surender; Weichselbaum, Ralph R.; Küfe, Donald

doi:10.1177/1947601910368059

Cited by 25 publications

(24 citation statements)

References 48 publications

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“…4 As found in the ATM-deficient mice, the size of the hematopoietic cell compartment was restored in the FoxOdeficient mice by treatment with NAC. 4,27 MUC1-C participates in stress-induced activation of ATM 29 and FoxO3a 19 and, thus, inhibition of MUC1-C in AML cells could also increase ROS and block self-renewal by affecting these pathways.…”

Section: Muc1-c Confers Aml Cell Survival By a Ros-dependent Mechanismmentioning

confidence: 99%

MUC1-C oncoprotein suppresses reactive oxygen species–induced terminal differentiation of acute myelogenous leukemia cells

Avigan

et al. 2011

Blood

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IntroductionAcute myelogenous leukemia (AML) is a clonal disorder of hematopoietic progenitor cells that is characterized by accumulation of blasts with an unrestrained proliferative capacity and a block at various stages of myeloid differentiation. 1 The development of AML involves a multistep process with the acquisition of alterations in genes that confer a proliferative advantage or affect differentiation. 2 Allogeneic bone marrow transplantation and therapy with cytosine arabinoside and daunorubicin have had a significant effect on long-term survival of AML patients younger than age 60. However, patients older than age 60 and those with secondary AML or a previous myelodysplastic syndrome have a poor prognosis. The concept that AML occurs as a result of a block in maturation has led to therapeutic approaches based on the use of agents that induce terminal AML cell differentiation. However, such strategies have been limited, in terms of effectiveness, to the treatment of acute promyelocytic leukemia (APL). For example, all-trans retinoic acid (ATRA) and arsenic trioxide induce differentiation of APL cells and have had a marked effect on the treatment of this disease. 3 Other studies have provided support for the involvement of reactive oxygen species (ROS) in the regulation of AML cell survival and induction of myeloid cell differentiation. 4 In this context, AML cell self-renewal is decreased by agents that increase ROS levels. [5][6][7] Moreover, differentiation of AML cells has been associated with increases in ROS. 8 These findings have suggested that targeting redox balance may overcome the block in terminal AML cell differentiation.The MUC1 heterodimeric protein is aberrantly expressed in blasts from patients with AML. 9,10 MUC1 includes an extracellular N-terminal subunit (MUC1-N) that has the structural characteristics of mucins and is tethered to the cell surface in a complex with a C-terminal transmembrane subunit (MUC1-C). 11 MUC1-C consists of a 58-amino acid extracellular domain, a transmembrane domain, and a 72-amino acid cytoplasmic domain. 11 In transformed cells with up-regulation of MUC1 expression, the MUC1-C subunit accumulates in the cytoplasm and is targeted to the nucleus and mitochondria. 11 The MUC1-C cytoplasmic domain is phosphorylated by c-Src and certain receptor tyrosine kinases, and interacts with effectors, such as ␤-catenin and NF-B, that have been linked to transformation. 11 Notably in this regard, the MUC1-C cytoplasmic domain is sufficient to induce anchorage-independent growth and tumorigenicity. 12 Overexpression of MUC1-C also blocks death induced in the response to DNA damage, ROS, and other forms of stress. 11,13,14 Targeting of MUC1-C to the nucleus and mitochondria, and thereby its transforming function, is dependent on the formation of oligomers through a CQC motif in the MUC1-C cytoplasmic domain. 11,15 These observations led to the development of cell-penetrating peptides that bind to the CQC motif and block MUC1-C oligomerization and function. 16 Moreover, trea...

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Section: Muc1-c Confers Aml Cell Survival By a Ros-dependent Mechanismmentioning

confidence: 99%

MUC1-C oncoprotein suppresses reactive oxygen species–induced terminal differentiation of acute myelogenous leukemia cells

Avigan

et al. 2011

Blood

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“…These functions allow MUC1 to facilitate tumor cell growth, invasion, motility, and cell survival under harsh conditions. Furthermore, MUC1 mediates DNA damage response by interacting with ataxia telangiectasia mutated (ATM) in breast cancer cells (16). MUC1 also interacts with c-Abl and prevents its nuclear targeting to block DNA damage-induced apoptosis (17).…”

Section: Introductionmentioning

confidence: 99%

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

Gunda

Souchek

Abrego

et al. 2017

Clinical Cancer Research

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Purpose MUC1, an oncogene overexpressed in multiple solid tumors including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models. Experimental design We used MUC1 knockdown and overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response and metabolomic evaluations. We also investigated if inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance using in vitro and in vivo models. Results MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pre-treatment with the glycolysis inhibitor, 3-bromopyruvate (BrPA) abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pre-treatment with nucleoside pools. Conclusions MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation-resistance in pancreatic cancer and targeted effectively through glycolytic inhibition.

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“…We focused our study on 24 radiation responsive ERP29 ERP29 candidate genes because these genes were previously documented to be connected with functions intimately linked to cancer (Table 2). [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Among the 24 genes, observations from previous studies noted post CT changes within 1 hour after radiation in 11 genes with 4 of them (ATM, ERP29, TP53, CDKN2A) showing post CT changes from very low radiation doses, as low as 0.1 Gy. Owing to their higher radiosensitivity, children are expected to react more sensitively than adults to the CT-induced radiation insult, and therefore, we included all 24 genes in our study, although some observations were reported longer than 1 hr post CT or after IR doses higher than those used in our study.…”

Section: Discussionmentioning

confidence: 99%

Changes in Whole Blood Gene Expression after Computed Tomography in Children: A Pilot Study

Halm

Tiirikainen²,

Lai³

et al. 2015

Gene Expression to Genetical Genomics

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ABSTRACT:Computed tomography (CT) exposes patients to ionizing X-irradiation (IR) that can alter the expression of genes responsible for controlling complex regulatory pathways. We sought to determine trends in the expression of 24 documented radiation-responsive genes linked to cancer in vivo. A total of 17 children (0.25-6 years old) undergoing medically indicated CT examinations with radiation doses ranging from 92.46 to 525.55 mGy cm (equivalent to effective doses of 0.78-11.30 mSv) were enrolled. Blood was drawn immediately before and 1 hour after their CT exams and mixed with an RNA additive for stabilization of gene expression. RNA samples of 14 of the 17 children were analyzed on a gene expression microarray. Absolute changes in gene expression were subtle, averaging less than 10%, but trends in expression changes of several genes were observed. ERP29, an endoplasmic reticulum chaperone, thought to be involved in the folding of secretory proteins, showed significant change in expression (8% decrease, P = 0.002) in the expected direction consistent with previous literature. PCNA expression increased linearly with CT dose (mGy cm) (P = 0.001). TP53 and FLT3LG expression increased linearly with effective dose (mSv) (P = 0.02 and P = 0.02). Previous IR exposure was associated with decreased GADD45A (P = 0.001) and FLT3LG (P = 0.03) and increased MDM2 expression (P = 0.02). We observed in this pilot study modest gene expression changes in the 24 IR-responsive candidate genes studied. Our results showed trends in gene expression changes, and they need to be confirmed in future studies with larger sample sizes to help develop risk assessments and preventive modalities for young patients undergoing CT.

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MUC1-C Oncoprotein Interacts Directly with ATM and Promotes the DNA Damage Response to Ionizing Radiation

Cited by 25 publications

References 48 publications

MUC1-C oncoprotein suppresses reactive oxygen species–induced terminal differentiation of acute myelogenous leukemia cells

MUC1-C oncoprotein suppresses reactive oxygen species–induced terminal differentiation of acute myelogenous leukemia cells

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

Changes in Whole Blood Gene Expression after Computed Tomography in Children: A Pilot Study

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