Proteasome inhibitor MG-132 reverses acquired resistance to TRAIL in human colon cancer cells

doi:10.3872/j.issn.1007-385X.2009.2.008

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Archive > Volume 16 Issue 2 > 2009,16(2):140-144. DOI:10.3872/j.issn.1007-385X.2009.2.008 Prev Next

Basic Research

Proteasome inhibitor MG-132 reverses acquired resistance to TRAIL in human colon cancer cells

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Abstract:

Objective: To evaluate the role of proteasome inhibitor MG132 in reversing the acquired TRAIL resistance of human colon cancer cell line DLD1TRAIL/R and the related mechanisms. Methods:Colon cancer cell line DLD1TRAIL/Rwas treated with MG132 combined with TRAIL protein. The viability of DLD1TRAIL/R cells was determined by MTT assay; the apoptotic rate was detected by flow cytometry, and the expression of apoptosisrelated proteins was examined by Western blotting analysis. Results: The viability of DLD1TRAIL/R cells was dramatically decreased after combined treatment with MG132 and TRAIL protein(P<0.01) and the apoptotic rate was significantly increased (P<0.01). Western blotting analysis showed that MG132 dramatically enhanced the cleavage of apoptotic molecules, including caspases8, 9, 3, Bid, and PARP in DLD1TRAIL/R cells after combined treatment and increased the release of cytochrome C and Smac from mitochondria. Further study demonstrated that MG132 upregulated DR5 and Bik proteins, but had no detectable effects on DR4, Bax, Bak, BclXL, XIAP or survivin. Moreover, we found MG132 induced phosphorylation of kinase JNK, and the inhibitor of JNK (SP600125) blocked MG132induced expression of DR5, but not the expression of Bik. Furthermore, SP600125 did not attenuate the apoptosis of DLD1TRAIL/R cells induced by MG132 in the presence of TRAIL protein (P<0.05). Conclusion: Proteasome inhibitor MG132 can reverse the acquired drug resistance to TRAIL and induce upregulation of DR5 and Bik protein in DLD1TRAIL/R cells. The underlying mechanism may involve the initiation of mitochondrionrelated apoptosis caused by Bik protein expression, not by activation of JNK pathway.

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Supported by the National Natural Science Foundation of China(No．30700970)；the Natural Science Foundation of Zhejiang Province(No．Y205093)

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