Abstract: Multidrug resistance (MDR) is the major impediment to cancer chemotherapy. The expression of lung resistance-related protein (LRP), a non-ATP-binding cassette (ABC) transporter, is high in tumor cells, resulting in their resistance to a variety of cytotoxic drugs. However, the function of LRP in tumor drug resistance is not yet explicit. Our previous studies had shown that Kinesin KIF4A was overexpressed in cisplatin (DDP)-resistant human lung adenocarcinoma cells (A549/DDP cells) compared with A549 cells. The expression of KIF4A in A549 or A549/DDP cells significantly affects cisplatin resistance but the detailed mechanisms remain unclear. Here, we performed co-immunoprecipitation experiments to show that the tail domain of KIF4A interacted with the N-terminal of LRP. Immunofluorescence images showed that both the ability of binding to LRP and the motility of KIF4A were essential for the dispersed cytoplasm distribution of LRP. Altogether, our results shed light on a potential mechanism in that motor protein KIF4A promotes drug resistance of lung adenocarcinoma cells through transporting LRP-based vaults along microtubules towards the cell membrane. Thus KIF4A might be a cisplatin resistance-associated protein and serves as a potential target for chemotherapeutic drug resistance in lung cancer.

驱动蛋白KIF4A通过调节肺耐药相关蛋白LRP的胞内运输参与肿瘤耐药

[1]Chung, J.H., Ginn-Pease, M.E., Eng, C., 2005. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has nuclear localization signal-like sequences for nuclear import mediated by major vault protein. Cancer Res., 65(10):4108-4116.

[2]Germann, U.A., 1996. P-glycoprotein—a mediator of multidrug resistance in tumour cells. Eur. J. Cancer, 32(6):927-944.

[3]Gottesman, M.M., Fojo, T., Bates, S.E., 2002. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer, 2(1):48-58.

[4]Han, M., Lv, Q., Tang, X.J., et al., 2012. Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine-hyaluronic acid complex. J. Control. Release, 163(2):136-144.

[5]Kathawala, R.J., Gupta, P., Ashby, C.R., et al., 2015. The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist. Updat., 18:1-17.

[6]Kickhoefer, V.A., Poderycki, M.J., Chan, E.K., et al., 2002. The La RNA-binding protein interacts with the vault RNA and is a vault-associated protein. J. Biol. Chem., 277(43):41282-41286.

[7]Martinez, N.W., Xue, X., Berro, R.G., et al., 2008. Kinesin KIF4 regulates intracellular trafficking and stability of the human immunodeficiency virus type 1 Gag polyprotein. J. Virol., 82(20):9937-9950.

[8]Midorikawa, R., Takei, Y., Hirokawa, N., 2006. KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity. Cell, 125(2):371-383.

[9]Mossink, M.H., van Zon, A., Franzel-Luiten, E., et al., 2002. Disruption of the murine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res., 62(24):7298-7304.

[10]Mossink, M.H., van Zon, A., Scheper, R.J., et al., 2003. Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene, 22(47):7458-7467.

[11]Scheffer, G.L., Wijngaard, P.L., Flens, M.J., et al., 1995. The drug resistance-related protein LRP is the human major vault protein. Nat. Med., 1(6):578-582.

[12]Scheffer, G.L., Schroeijers, A.B., Izquierdo, M.A., et al., 2000. Lung resistance-related protein/major vault protein and vaults in multidrug-resistant cancer. Curr. Opin. Oncol., 12(6):550-556.

[13]Scheper, R.J., Broxterman, H.J., Scheffer, G.L., et al., 1993. Overexpression of a M(r) 110 000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res., 53(7):1475-1479.

[14]Slesina, M., Inman, E.M., Moore, A.E., et al., 2006. Movement of vault particles visualized by GFP-tagged major vault protein. Cell Tissue Res., 324(3):403-410.

[15]Steiner, E., Holzmann, K., Elbling, L., et al., 2006. Cellular functions of vaults and their involvement in multidrug resistance. Curr. Drug Targets, 7(8):923-934.

[16]Taniwaki, M., Takano, A., Ishikawa, N., et al., 2007. Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer. Clin. Cancer Res., 13(22):6624-6631.

[17]Trussardi, A., Poitevin, G., Gorisse, M.C., et al., 1998. Sequential overexpression of LRP and MRP but not P-gp 170 in VP16-selected A549 adenocarcinoma cells. Int. J. Oncol., 13(3):543-548.

[18]van Zon, A., Mossink, M.H., Schoester, M., et al., 2002. Structural domains of vault proteins: a role for the coiled coil domain in vault assembly. Biochem. Biophys. Res. Commun., 291(3):535-541.

[19]van Zon, A., Mossink, M.H., Houtsmuller, A.B., et al., 2006. Vault mobility depends in part on microtubules and vaults can be recruited to the nuclear envelope. Exp. Cell Res., 312(3):245-255.

[20]Wandke, C., Barisic, M., Sigl, R., et al., 2012. Human chromokinesins promote chromosome congression and spindle microtubule dynamics during mitosis. J. Cell Biol., 198(5):847-863.

[21]Willemsen, M.H., Ba, W., Wissink-Lindhout, W.M., et al., 2014. Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function. J. Med. Genet., 51(7):487-494.

[22]Wu, G., Zhou, L., Khidr, L., et al., 2008. A novel role of the chromokinesin Kif4A in DNA damage response. Cell Cycle, 7(13):2013-2020.

[23]Xiao, N., Fu, C.H., Lin, Y.N., et al., 2016. Overexpression of chromosome kinesin protein KIF4A enhance cisplatin resistance in A549/DDP cells. Int. J. Clin. Exp. Pathol., 9(3):3331-3339.

[24]Yang, J., Kickhoefer, V.A., Ng, B.C., et al., 2010. Vaults are dynamically unconstrained cytoplasmic nanoparticles capable of half vault exchange. ACS Nano, 4(12):7229-7240.

[25]Yu, Z., Fotouhi-Ardakani, N., Wu, L., et al., 2002. PTEN associates with the vault particles in HeLa cells. J. Biol. Chem., 277(43):40247-40252.

[26]Zhang, W., Zhou, H., Yu, Y., et al., 2016. Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression. OncoTargets Ther., 9:3359-3368.

[27]Zhu, C., Jiang, W., 2005. Cell cycle-dependent translocation of PRC1 on the spindle by Kif4 is essential for midzone formation and cytokinesis. Proc. Natl. Acad. Sci. USA, 102(2):343-348.

[28]Zhu, C., Zhao, J., Bibikova, M., et al., 2005. Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. Mol. Biol. Cell, 16(7):3187-3199.

[29]Zhu, C.L., Cheng, D.Z., Liu, F., et al., 2015. Hepatitis B virus upregulates the expression of kinesin family member 4A. Mol. Med. Rep., 12(3):3503-3507.

[30]List of electronic supplementary materials

[31]Fig. S1 mRNA and protein expression of LRP and KIF4A in A549 and A549/DDP cells