Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex via Activation of Unfolded Protein Response

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  • Matsumura Kazushi
    Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Sakai Chika
    Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Kawakami Shigeru
    Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Yamashita Fumiyoshi
    Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Hashida Mitsuru
    Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University Institute for Integrated Cell-Material Science (iCeMS), Kyoto University

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  • Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

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Proteasome inhibitors are a novel class of molecular-targeted anti-cancer drugs that suppress the degradation of malfolded proteins, trigger endoplasmic reticulum (ER) stress, and activate apoptosis signals. Glucose-regulated protein 78 (GRP78), a major ER chaperone, is one of the most important molecules for transduction of unfolded protein response (UPR) signals. In accordance with past findings that expression of GRP78 is elevated in cancer cells and helps to resist stress-induced apoptosis, GRP78 knockdown could be effective in anticancer therapy. We tested this hypothesis and found that transfection of small interfering RNA (siRNA) targeting GRP78 inhibited the growth of RENCA renal carcinoma cells, in association with elevated gene expression of UPR downstream signaling molecules (CHOP, EDEM1, and ERdj4 mRNA). In addition, the combinatorial effect of GRP78 siRNA with ER stress inducers (tunicamycin, MG132, and 2-deoxyglucose) on survival was measured. Combination of GRP78 siRNA and the ER stress inducers more extensively reduced cell viability than combination with scrambled siRNA. Besides RENCA, B16BL6 melanoma cells were also shown to be sensitive to GRP78 siRNA. These results suggest that GRP78 knockdown might be an effective strategy for cancer therapy targeting UPR-induced apoptosis.

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