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GRP78 regulates sensitivity of human colorectal cancer cells to DNA targeting agents

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Abstract

This study was carried out to investigate the activation status of unfolded protein response (UPR) in colorectal cancer (CRC) and its contribution to CRC resistance to chemotherapy-induced apoptosis. Chemotherapy-induced apoptosis was assessed by the propidium iodide method. Activation of UPR was evaluated in CRC cell lines using immunoblotting technique and in CRC tissues using immunohistochemistry. Findings of the present study revealed that the UPR is constitutively activated in CRC cell lines and CRC tissues isolated from patients, as evidenced by relatively high levels of the 78-kDa glucose-regulated protein (GRP78) and spliced X-box-binding protein 1 mRNA in tissue samples. In addition, CRC cell lines differentially responded to clinically relevant DNA-targeting agents including cisplatin, and 5-flourouracil. Moreover, the levels of GRP78 were inversely associated with sensitivity of CRC cells to chemotherapy-induced apoptosis. Inhibition of GRP78 by siRNA resulted in increased sensitivity of CRC cells to chemotherapeutic agents. Collectively, current results appear to provide novel insights into the role of UPR in determining sensitivity of CRC cells to chemotherapeutic agents and might have important implications for personalized CRC treatment.

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Acknowledgments

We would like to acknowledge the Scientific Research Support Fund at Ministry of Higher Education and Scientific Research, Amman, Jordan, for the financial support (Grant number 118-2011).

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Authors confirm that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan

    Nizar M. Mhaidat, Karem H. Alzoubi & Qosay A. Al-Balas

  2. Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan

    Omar F. Khabour

  3. Faculty of Science, Taibah University, Almadina, Saudi Arabia

    Omar F. Khabour

  4. Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan

    Mohammed N. Banihani & Sulaiman Swaidan

Authors
  1. Nizar M. Mhaidat
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  2. Karem H. Alzoubi
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  3. Omar F. Khabour
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  4. Mohammed N. Banihani
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  5. Qosay A. Al-Balas
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  6. Sulaiman Swaidan
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Correspondence to Nizar M. Mhaidat.

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Mhaidat, N.M., Alzoubi, K.H., Khabour, O.F. et al. GRP78 regulates sensitivity of human colorectal cancer cells to DNA targeting agents. Cytotechnology 68, 459–467 (2016). https://doi.org/10.1007/s10616-014-9799-8

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  • DOI: https://doi.org/10.1007/s10616-014-9799-8

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