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A low cost PS based microfluidic platform to investigate cell cycle towards developing a therapeutic strategy for cancer

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Abstract

Inhibition of DNA damage response pathway in combination with DNA alkylating agents may enhance the selective killing of cancer cells leading to better therapeutic effects. MDM2 binding protein (MTBP) in human has a role in G1 phase (interphase of cell cycle) and its overexpression leads to breast and ovarian cancers. Sld7 is an uncharacterized protein in budding yeast and a potential functional homologue of MTBP. To investigate the role of Sld7 as a therapeutic target, the behavior of the wild-type cells and sld7∆ mutants were monitored in 0.5 nL microbioreactors. The brightfield microscopy images were used to analyze the change in the cell size and to determine the durations of G1 and S/G2/M phases of wild type cells and mutants. With the administration of the alkylating agent, the cell size decreased and the duration of cell cycle increased. The replacement of the medium with the fresh one enabled the cells to repair their DNA. The application of calorie restriction together with DNA alkylating agent to mutant cells resulted in smaller cell size and longer G1 phase compared to those in control environment. For therapeutic purposes, the potential of MTBP in humans or Sld7 in yeast as a drug target deserves further exploration. The fabrication simplicity, robustness and low-cost of this microfluidic bioreactor made of polystyrene allowed us to perform yeast culturing experiments and show a potential for further cell culturing studies. The device can successfully be used for therapeutic applications including the discovery of new anti-microbial, anti-inflammatory, anti-cancer drugs.

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References

  • R.C. Alver, G.S. Chadha, J.J. Blow, DNA Repair (Amst) 19, 182 (2014)

    Article  Google Scholar 

  • H. Araki, Genes Genet. Syst. 86, 141 (2011)

    Article  Google Scholar 

  • H. Becker, C. Gärtner, Electrophoresis 21, 12 (2000)

    Article  Google Scholar 

  • S.N. Bhatia, D.E. Ingber, Nat. Biotechnol. 32, 760 (2014)

    Article  Google Scholar 

  • A. Bhattacharyya, C.M. Klapperich, Lab Chip 7, 876 (2007)

    Article  Google Scholar 

  • D. Boos, M. Yekezare, J.F.X. Diffley, Science 340, 981 (2013)

    Article  Google Scholar 

  • B.J. Brewer, E. Chlebowicz-Sledziewska, W.L. Fangman, Mol. Cell. Biol. 4, 2529 (1984)

    Article  Google Scholar 

  • B. Brujins, A. van Asten, R. Tiggelaar, H. Gardeniers, Biosensors 6, 1 (2016)

    Article  Google Scholar 

  • I. Caffa, V. D’Agostino, P. Damonte, D. Soncini, M. Cea, F. Monacelli, P. Odetti, A. Ballestrero, A. Provenzani, V.D. Longo, A. Nencioni, Oncotarget 6, 11820 (2015)

    Article  Google Scholar 

  • Y. Cao, J. Bontrager-Singer, L. Zhu, J. Micromech. Microeng. 25, 065005 (2015)

    Article  Google Scholar 

  • A. Chandrasekaran, N. Kalashnikov, R. Rayes, C. Wang, J. Spicer, C. Moraes, Lab Chip 17, 2003 (2017)

    Article  Google Scholar 

  • C.-S. Chen, D.N. Breslauer, J.I. Luna, A. Grimes, W.C. Chin, L.P. Lee, M. Khine, Lab Chip 8, 622 (2008)

    Article  Google Scholar 

  • H. Chen, W. Yao, Q. Chu, R. Han, Y. Wang, J. Sun, D. Wang, Y. Wang, M. Cao, Y. He, Cancer Lett. 369, 97 (2015)

    Article  Google Scholar 

  • M.M. Crane, I.B.N. Clark, E. Bakker, S. Smith, P.S. Swain, PLoS One 9, 1 (2014)

    Google Scholar 

  • I.E. Dayan, K.Y. Arga, K.O. Ulgen, Omi. A J. Integr. Biol. 21, 100 (2017)

    Article  Google Scholar 

  • S. Di Biase, C. Lee, S. Brandhorst, B. Manes, R. Buono, C. Cheng, M. Cacciottolo, A. Martin-Montalvo, R. de Cabo, M. Wei, T.E. Morgan, V.D. Longo, Cancer Cell 30, 136 (2016)

    Article  Google Scholar 

  • S. Di Talia, J.M. Skotheim, J.M. Bean, E.D. Siggia, F.R. Cross, Nature 448, 947 (2007)

    Article  Google Scholar 

  • F. Ferrezuelo, N. Colomina, A. Palmisano, E. Garí, C. Gallego, A. Csikász-Nagy, M. Aldea, Nat. Commun. 3, 1012 (2012)

    Article  Google Scholar 

  • E. Gencturk, S. Mutlu, K.O. Ulgen, Biomicrofluidics 11, 051502 (2017)

    Article  Google Scholar 

  • B.C. Grieb, X. Chen, C.M. Eischen, Mol. Cancer Res. 12, 1216 (2014)

    Article  Google Scholar 

  • P. Groth, S. Ausländer, M.M. Majumder, N. Schultz, F. Johansson, E. Petermann, T. Helleday, J. Mol. Biol. 402, 70 (2010)

    Article  Google Scholar 

  • J.I. Hahm, Langmuir 30, 9891 (2014)

    Article  Google Scholar 

  • S. Halldorsson, E. Lucumi, R. Gómez-Sjöberg, R.M.T. Fleming, Biosens. Bioelectron. 63, 218 (2015)

    Article  Google Scholar 

  • D. Hanway, J.K. Chin, G. Xia, G. Oshiro, E.A. Winzeler, F.E. Romesberg, Proc. Natl. Acad. Sci. U. S. A. 99, 10605 (2002)

    Article  Google Scholar 

  • R.W. Hart, A. Turturro, Environ. Health Perspect. 105, 989 (1997)

    Google Scholar 

  • Z.X. He, Z.H. Sun, W.Z. Yang, K.A. Beauchemin, S.X. Tang, C.S. Zhou, X.F. Han, M. Wang, J.H. Kang, Z.L. Tan, J. Anim. Sci. 92, 4856 (2014)

    Article  Google Scholar 

  • T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R.A. Sharma, Nat. Rev. Cancer 8, 193 (2008)

    Article  Google Scholar 

  • X. Hu, Y. Dong, Q. He, H. Chen, Z. Zhu, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 990, 96 (2015)

    Article  Google Scholar 

  • R.M. Jones, E. Petermann, Biochem. J. 443, 13 (2012)

    Article  Google Scholar 

  • P. Jorgensen, J.L. Nishikawa, B. Breitkreutz, M. Tyers, Science 297, 395 (2002)

    Article  Google Scholar 

  • N. Kim, S.N. Huang, J.S. Williams, Y.C. Li, A.B. Clark, J. Cho, T.A. Kunkel, Y. Pommier, S. Jinks-Robertson, Science 332, 1561 (2011)

    Article  Google Scholar 

  • R. Kodzius, K. Xiao, J. Wu, X. Yi, X. Gong, I.G. Foulds, W. Wen, Sensors Actuators B Chem. 161, 349 (2012)

    Article  Google Scholar 

  • K. Köhler, P. Ferreira, B. Pfander, D. Boos, Springer, Chapter 22 (2016)

  • G.S. Kopeina, V.V. Senichkin, B. Zhivotovsky, Biochim. Biophys. Acta. 1867, 29 (2017)

    Google Scholar 

  • O.V. Leontieva, M.V. Blagosklonny, Aging (Albany NY) 3, 1078 (2011)

    Article  Google Scholar 

  • D. Mcintosh, J.J. Blow, Cold Spring Harb. Perspect. Biol. 4, a012955 (2012)

    Article  Google Scholar 

  • M. Mehling, S. Tay, Curr. Opin. Biotechnol. 25, 95 (2014)

    Article  Google Scholar 

  • R. Milo, R. Philips, Cell biology by the numbers, 1st edn. (Garland Science, 2015)

  • V.C. Miranda, M.I. Braghiroli, L.D. Faria, G. Bariani, A. Alex, J.E. Bezerra Neto, F.C. Capareli, J. Sabbaga, J.F. Lobo dos Santos, P.M. Hoff, R.P. Riechelmann, Clin. Colorectal Cancer 15, 321 (2016)

    Article  Google Scholar 

  • A.G. Paulovich, L.H. Hartwell, Cell 82, 841 (1995)

    Article  Google Scholar 

  • F. Pietrocola, J. Pol, E. Vacchelli, S. Rao, D.P. Enot, E.E. Baracco, S. Levesque, F. Castoldi, N. Jacquelot, T. Yamazaki, L. Senovilla, G. Marino, F. Aranda, S. Durand, V. Sica, A. Chery, S. Lachkar, V. Sigl, N. Bloy, A. Buque, S. Falzoni, B. Ryffel, L. Apetoh, F. Di Virgilio, F. Madeo, M.C. Maiuri, L. Zitvogel, B. Levine, J.M. Penninger, G. Kroemer, Cancer Cell 30, 147 (2016)

    Article  Google Scholar 

  • S. Puza, E. Gencturk, I.E. Odabasi, E. Iseri, S. Mutlu, K.O. Ulgen, Biomed. Microdevices 19 (2017)

  • R. Ralhan, J. Kaur, J. Expert Opin. Ther. Patents 17, 1061 (2007)

    Article  Google Scholar 

  • C. Santocanale, J.F. Diffley, Nature 395, 615 (1998)

    Article  Google Scholar 

  • F. Sherman, Encycl. Mol. Biol. Mol. Medicine 6, 302 (1997)

    Google Scholar 

  • K. Shirahige, Y. Hori, K. Shiraishi, M. Yamashita, K. Takahashi, C. Obuse, T. Tsurimoto, H. Yoshikawa, Nature 395, 618 (1998)

    Article  Google Scholar 

  • K. Sun, Y. Xie, D. Ye, Y. Zhao, Y. Cui, F. Long, W. Zhang, X. Jiang, Langmuir 28, 2131 (2012)

    Article  Google Scholar 

  • S. Tanaka, R. Nakato, Y. Katou, K. Shirahige, H. Araki, Curr. Biol. 21, 2055 (2011a)

    Article  Google Scholar 

  • T. Tanaka, T. Umemori, S. Endo, S. Muramatsu, M. Kanemaki, Y. Kamimura, C. Obuse, H. Araki, EMBO J. 30, 2019 (2011b)

    Article  Google Scholar 

  • M. Tehranirokh, A.Z. Kouzani, P.S. Francis, J.R. Kanwar, Biomicrofluidics 7, 51502 (2013)

    Article  Google Scholar 

  • J.A. Tercero, J.F.X. Diffley, Nature 412, 553 (2001)

    Article  Google Scholar 

  • P.M. van Midwoud, A. Janse, M.T. Merema, G.M.M. Groothuis, E. Verpoorte, Anal. Chem. 84, 3938 (2012)

    Article  Google Scholar 

  • M. Werner, F. Merenda, J. Piguet, R.P. Salathé, H. Vogel, Lab Chip 11, 2432–2439 (2011)

    Article  Google Scholar 

  • M. Yekezare, B. Gomez-Gonzalez, J.F.X. Diffley, J. Cell Sci. 126, 1297 (2013)

    Article  Google Scholar 

  • L.Y. Yeo, H.C. Chang, P.P. Chan, J.R. Friend, Small 7(1), 12–48 (2011)

    Article  Google Scholar 

  • E.W.K. Young, E. Berthier, D.J. Guckenberger, E. Sackmann, C. Lamers, I. Meyvantsson, A. Huttenlocher, D.J. Beebe, Anal. Chem. 83, 1408 (2011)

    Article  Google Scholar 

  • E.B. Yucel, S. Eraslan, K.O. Ulgen, FEBS J. 281, 1281 (2014)

    Article  Google Scholar 

  • P. Zegerman, J.F.X. Diffley, Nature 467, 474 (2010)

    Article  Google Scholar 

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Acknowledgements

The financial support of Boğaziçi University Research Fund through project 11141 M was gratefully acknowledged.

Funding

This study was funded by Boğaziçi University Research Fund through project 11141 M.

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Correspondence to Kutlu O. Ulgen.

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“This article does not contain any studies with human participants or animals performed by any of the authors.”

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Odabasi, I.E., Gencturk, E., Puza, S. et al. A low cost PS based microfluidic platform to investigate cell cycle towards developing a therapeutic strategy for cancer. Biomed Microdevices 20, 57 (2018). https://doi.org/10.1007/s10544-018-0302-8

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