Enhanced DNA damage response through RAD50 in triple negative breast cancer resistant and cancer stem-like cells contributes to chemoresistance
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
33090711
DOI
10.1111/febs.15588
Knihovny.cz E-resources
- Keywords
- DNA damage repair, RAD50, cancer stem cells, chemoresistance, triple-negative breast cancer,
- MeSH
- Drug Resistance, Neoplasm drug effects genetics MeSH
- Cisplatin administration & dosage MeSH
- Cyclophosphamide administration & dosage MeSH
- DNA-Binding Proteins genetics MeSH
- Doxorubicin administration & dosage MeSH
- DNA Repair Enzymes genetics MeSH
- MRE11 Homologue Protein genetics MeSH
- Acid Anhydride Hydrolases genetics MeSH
- Nuclear Proteins genetics MeSH
- Humans MeSH
- Neoplastic Stem Cells drug effects metabolism MeSH
- DNA Damage drug effects MeSH
- Disease-Free Survival MeSH
- Cell Cycle Proteins genetics MeSH
- Triple Negative Breast Neoplasms drug therapy genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cisplatin MeSH
- Cyclophosphamide MeSH
- DNA-Binding Proteins MeSH
- Doxorubicin MeSH
- DNA Repair Enzymes MeSH
- MRE11 Homologue Protein MeSH
- Acid Anhydride Hydrolases MeSH
- Nuclear Proteins MeSH
- MRE11 protein, human MeSH Browser
- NBN protein, human MeSH Browser
- Cell Cycle Proteins MeSH
- RAD50 protein, human MeSH Browser
A growing body of evidence supports the notion that cancer resistance is driven by a small subset of cancer stem cells (CSC), responsible for tumor initiation, growth, and metastasis. Both CSC and chemoresistant cancer cells may share common qualities to activate a series of self-defense mechanisms against chemotherapeutic drugs. Here, we aimed to identify proteins in chemoresistant triple-negative breast cancer (TNBC) cells and corresponding CSC-like spheroid cells that may contribute to their resistance. We have identified several candidate proteins representing the subfamilies of DNA damage response (DDR) system, the ATP-binding cassette, and the 26S proteasome degradation machinery. We have also demonstrated that both cell types exhibit enhanced DDR when compared to corresponding parental counterparts, and identified RAD50 as one of the major contributors in the resistance phenotype. Finally, we have provided evidence that depleting or blocking RAD50 within the Mre11-Rad50-NBS1 (MRN) complex resensitizes CSC and chemoresistant TNBC cells to chemotherapeutic drugs.
Department of Experimental and Health Sciences Universitat Pompeu Fabra Barcelona Spain
National Centre for Biomolecular Research Faculty of Science Masaryk University Brno Czech Republic
See more in PubMed
Shibue T & Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14, 611-629.
Beck B & Blanpain C (2013) Unravelling cancer stem cell potential. Nat Rev Cancer 13, 727-738.
Zhao J (2016) Cancer stem cells and chemoresistance: the smartest survives the raid. Pharmacol Ther 160, 145-158.
Steg AD, Bevis KS, Katre AA, Ziebarth A, Dobbin ZC, Alvarez RD, Zhang K, Conner M & Landen CN (2012) Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res 18, 869-881.
Izumiya M, Kabashima A, Higuchi H, Igarashi T, Sakai G, Iizuka H, Nakamura S, Adachi M, Hamamoto Y, Funakoshi S et al. (2012) Chemoresistance is associated with cancer stem cell-like properties and epithelial-to-mesenchymal transition in pancreatic cancer cells. Anticancer Res 32, 3847-3853.
Lee HE, Kim JH, Kim YJ, Choi SY, Kim S-W, Kang E, Chung IY, Kim IA, Kim EJ, Choi Y et al. (2011) An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 104, 1730-1738.
Hopfner KP, Karcher A, Shin DS, Craig L, Arthur LM, Carney JP & Tainer JA (2000) Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101, 789-800.
Ruan Z, Liu J & Kuang Y (2015) Isolation and characterization of side population cells from the human ovarian cancer cell line SK-OV-3. Exp Ther Med 10, 2071-2078.
Kruger JA, Kaplan CD, Luo Y, Zhou H, Markowitz D, Xiang R & Reisfeld RA (2006) Characterization of stem cell-like cancer cells in immune-competent mice. Blood 108, 3906-3912.
Abad E, Graifer D & Lyakhovich A (2020) DNA damage response and resistance of cancer stem cells. Cancer Lett 474, 106-117.
Cidado J, Wong HY, Marc Rosen D, Cimino-Mathews A, Garay JP, Fessler AG, Rasheed ZA, Hicks J, Cochran RL, Croessmann S et al. (2016) Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget 7, 6281-6293.
Bogliolo M, Lyakhovich A, Callén E, Castellà M, Cappelli E, Ramírez MJ, Creus A, Marcos R, Kalb R, Neveling K et al. (2007) Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability. EMBO J 26, 1340-1351.
Cleaver JE, Feeney L & Revet I (2011) Phosphorylated H2Ax is not an unambiguous marker for DNA double-strand breaks. Cell Cycle 10, 3223-3224.
Altan B, Yokobori T, Ide M, Bai T, Yanoma T, Kimura A, Kogure N, Suzuki M, Bao P, Mochiki E et al. (2016) High expression of MRE11-RAD50-NBS1 is associated with poor prognosis and chemoresistance in gastric cancer. Anticancer Res 36, 5237-5247.
Theunissen J-WF, Kaplan MI, Hunt PA, Williams BR, Ferguson DO, Alt FW & Petrini JHJ (2003) Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice. Mol Cell 12, 1511-1523.
Mao Z, Jiang Y, Liu X, Seluanov A & Gorbunova V (2009) DNA repair by homologous recombination, but not by nonhomologous end joining, is elevated in breast cancer cells. Neoplasia 11, 683-691.
Lee J-H (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304, 93-96.
Donahue SL & Campbell C (2004) A Rad50-dependent pathway of DNA repair is deficient in Fanconi anemia fibroblasts. Nucleic Acids Res 32, 3248-3257.
Pierce AJ, Johnson RD, Thompson LH & Jasin M (1999) XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev 13, 2633-2638.
Gatei M, Jakob B, Chen P, Kijas AW, Becherel OJ, Gueven N, Birrell G, Lee J-H, Paull TT, Lerenthal Y et al. (2011) ATM protein-dependent phosphorylation of Rad50 protein regulates DNA repair and cell cycle control. J Biol Chem 286, 31542-31556.
Abuzeid WM, Jiang X, Shi G, Wang H, Paulson D, Araki K, Jungreis D, Carney J, O'Malley BW & Li D (2009) Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy. J Clin Invest 119, 1974-1985.
Dupré A, Boyer-Chatenet L, Sattler RM, Modi AP, Lee J-H, Nicolette ML, Kopelovich L, Jasin M, Baer R, Paull TT et al. (2008) A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol 4, 119-125.
Garner KM, Pletnev AA & Eastman A (2009) Corrected structure of mirin, a small-molecule inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol 5, 129-130.
Shibata A, Moiani D, Arvai AS, Perry J, Harding SM, Genois MM, Maity R, van Rossum-Fikkert S, Kertokalio A, Romoli F et al. (2014) DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell 53, 7-18.
Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, Stanford J, Cook RS & Arteaga CL (2013) TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 123, 1348-1358.
Adelman CA, De S & Petrini JHJ (2009) Rad50 is dispensable for the maintenance and viability of postmitotic tissues. Mol Cell Biol 29, 483-492.
Ceccaldi R, Rondinelli B & D'Andrea AD (2016) Repair pathway choices and consequences at the double-strand break. Trends Cell Biol 26, 52-64.
King HO, Brend T, Payne HL, Wright A, Ward TA, Patel K, Egnuni T, Stead LF, Patel A, Wurdak H et al. (2017) RAD51 is a selective DNA repair target to radiosensitize glioma stem cells. Stem Cell Reports 8, 125-139.
Lim YC, Roberts TL, Day BW, Harding A, Kozlov S, Kijas AW, Ensbey KS, Walker DG & Lavin MF (2012) A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells. Mol Cancer Ther 11, 1863-1872.
Mathews LA, Cabarcas SM, Hurt EM, Zhang X, Jaffee EM & Farrar WL (2011) Increased expression of DNA repair genes in invasive human pancreatic cancer cells. Pancreas 40, 730-739.
Bartucci M, Svensson S, Romania P, Dattilo R, Patrizii M, Signore M, Navarra S, Lotti F, Biffoni M, Pilozzi E et al. (2012) Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy. Cell Death Differ 19, 768-778.
Cheng L, Wu Q, Huang Z, Guryanova OA, Huang Q, Shou W, Rich JN & Bao S (2011) L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J 30, 800-813.
Gemenetzidis E, Gammon L, Biddle A, Emich H & Mackenzie IC (2015) Invasive oral cancer stem cells display resistance to ionising radiation. Oncotarget 6, 43964-43977.
Vitale I, Manic G, De Maria R, Kroemer G & Galluzzi L (2017) DNA damage in stem cells. Mol Cell 66, 306-319.
Yin H & Glass J (2011) The phenotypic radiation resistance of CD44+/CD24(-or low) breast cancer cells is mediated through the enhanced activation of ATM signaling. PLoS One 6, e24080.
López-Saavedra A, Gómez-Cabello D, Domínguez-Sánchez MS, Mejías-Navarro F, Fernández-Ávila MJ, Dinant C, Martínez-Macías MI, Bartek J & Huertas P (2016) A genome-wide screening uncovers the role of CCAR2 as an antagonist of DNA end resection. Nat Commun 7, 1-14.
Roset R, Inagaki A, Hohl M, Brenet F, Lafrance-Vanasse J, Lange J, Scandura JM, Tainer JA, Keeney S & Petrini JHJ (2014) The Rad50 hook domain regulates DNA damage signaling and tumorigenesis. Genes Dev 28, 451-462.
Arthur LM, Gustausson K, Hopfner K-P, Carson CT, Stracker TH, Karcher A, Felton D, Weitzman MD, Tainer J & Carney JP (2004) Structural and functional analysis of Mre11-3. Nucleic Acids Res 32, 1886-1893.
Luo G, Yao MS, Bender CF, Mills M, Bladl AR, Bradley A & Petrini JHJ (1999) Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96, 7376-7381.
Abad E, García-Mayea Y, Mir C, Sebastian D, Zorzano A, Potesil D, Zdrahal Z, Lyakhovich A & Lleonart ME (2019) Common metabolic pathways implicated in resistance to chemotherapy point to a key mitochondrial role in breast cancer. Mol Cell Proteomics 18, 231-244.
Epanchintsev A, Shyamsunder P, Verma RS & Lyakhovich A (2015) IL-6, IL-8, MMP-2, MMP-9 are overexpressed in Fanconi anemia cells through a NF-κB/TNF-α dependent mechanism. Mol Carcinog 54, 1686-1699.
Esner M, Graifer D, Lleonart ME & Lyakhovich A (2017) Targeting cancer cells through antibiotics-induced mitochondrial dysfunction requires autophagy inhibition. Cancer Lett 384, 60-69.
Hill SJ, Clark AP, Silver DP & Livingston DM (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34, 3828-3842.
Artero-Castro A, Callejas FB, Castellvi J, Kondoh H, Carnero A, Fernández-Marcos PJ, Serrano M, Ramón y Cajal S & Lleonart ME(2009) Cold-inducible RNA-binding protein bypasses replicative senescence in primary cells through extracellular signal-regulated kinase 1 and 2 activation. Mol Cell Biol 29, 1855-1868.
Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q & Szallasi Z (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat 123, 725-731.
Lyakhovich A & Surrallés J (2010) Constitutive activation of caspase-3 and Poly ADP ribose polymerase cleavage in Fanconi anemia cells. Mol Cancer Res 8, 46-56.
Abad E, Samino S, Yanes O, Potesil D, Zdrahal Z & Lyakhovich A (2020) Activation of glycogenolysis and glycolysis in breast cancer stem cell models. Biochim Biophys Acta Mol Basis Dis 1866, 65886.
