Role of autophagy in chemoresistance: Regulation of the ATM-mediated DNA-damage signaling pathway through activation of DNA–PKcs and PARP-1

Yoon, Jung‐Hoon; Ahn, Sang‐Gun; Lee, Byung‐Hoon; Jung, Sung Soo; Oh, Seon-Hee

doi:10.1016/j.bcp.2011.12.029

Cited by 93 publications

(72 citation statements)

References 47 publications

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“…ROS signaling was also upstream of the ER-sensing proteins PERK and IRE1␣. In the literature, DNA damage has most often been reported to induce autophagy, with this autophagy generally having a protective role (Robert et al, 2011;Rodriguez-Rocha et al, 2011;Yoon et al, 2012). This is opposite our findings of ROS/autophagy stimulating DNA damage and autophagy being a toxic event.…”

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confidence: 99%

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

et al. 2012

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Previous studies showed that lapatinib and obatoclax interact in a greater-than-additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses. Lapatinib and obatoclax killed multiple tumor cell types, and cells lacking phosphatase and tensin homolog (PTEN) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null breast cancer cells restored drug sensitivity. Coadministration of lapatinib with obatoclax elicited autophagic cell death that was attributable to the actions of mitochondrial reactive oxygen species. Wild-type cells but not mitochondria-deficient rho-zero cells were radiosensitized by lapatinib and obatoclax treatment. Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase 1/2 (JNK1/2) by the drug combination was enhanced by radiation, and signaling by p38 MAPK and JNK1/2 promoted cell killing. In immunohistochemical analyses, the autophagosome protein p62 was determined to be associated with protein kinase-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1, as well as with binding immunoglobulin protein/78-kDa glucose-regulated protein, in drug combination-treated cells. Knockdown of PERK suppressed drug-induced autophagy and protected tumor cells from the drug combination. Knockdown of PERK suppressed the reduction in Mcl-1 expression after drug combination exposure, and overexpression of Mcl-1 protected cells. Our data indicate that mitochondrial function plays an essential role in cell killing by lapatinib and obatoclax, as well as radiosensitization by this drug combination.

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confidence: 99%

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

et al. 2012

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“…42 With regard to PRKDC, its connection to the autophagy pathway is less clear, albeit there is evidence suggesting the presence of such a link. 38,43,44 The mobilization of autophagy via these DDR transducers can be prosurvival 38,39,[45][46][47][48] or antisurvival; 38,39,48,49 and the dual roles that autophagy plays in cell fate determination under DNA damage stress conditions add to the complexity of its involvement in DDR, and may influence the outcome of anticancer chemotherapy. The interplay between DDR and autophagy is a burgeoning area of research in the autophagy field, linking autophagy with genomic integrity.…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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“…53,54 It is worth noting that autophagy activation was shown to precede phosphorylation of ATM and p53 and activation of DNA repair proteins in response to capsaicin treatment, revealing an intricate pathway in which autophagy acts upstream, and not just as a consequence, of DDR activation. 82 BNIP3 is a Bcl-2 homologous protein and is activated after conditions of stress such as hypoxia. MMR induced by 6-thioguanine activates autophagy through MLH1, p53 activation and transcription of bnip3.…”

Section: Pathways Connecting Ddr To Autophagymentioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

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DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

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Role of autophagy in chemoresistance: Regulation of the ATM-mediated DNA-damage signaling pathway through activation of DNA–PKcs and PARP-1

Cited by 93 publications

References 47 publications

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Autophagy and genomic integrity

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