Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells.
Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells.
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DOI：
10.3892/ijo.2011.1317
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发表时间：
2012-04
影响因子：
5.2
通讯作者：
Tomoda A
中科院分区：
文献类型：
--
作者：
Komatsu S;Miyazawa K;Moriya S;Takase A;Naito M;Inazu M;Kohno N;Itoh M;Tomoda A
特定的26S蛋白酶体抑制剂，硼替佐米（Bz）可能诱导凋亡以及自噬在转移性乳腺癌细胞系中，例如MDA-MB-231和MDA-MB-468。在这些细胞系中，尽管仅使用100μg/ml凸轮的治疗对细胞生长的抑制作用几乎没有影响使用25μg/mL CAM处理后，该结果表明凸轮阻止了自噬通量，但BZ和CAM的联合处理可导致更明显的自噬诱导单独使用BZ的细胞内p62清除。 GRP78。 CHOP敲除MEF细胞系完全消除了这种增强和对BZ治疗的耐药性。通过将这些试剂结合起来，涉及明显的细胞毒性。 。
The specific 26S proteasome inhibitor, bortezomib (BZ) potently induces apoptosis as well as autophagy in metastatic breast cancer cell lines such as MDA-MB-231 and MDA-MB-468. The combined treatment of clarithromycin (CAM) and BZ significantly enhances cytotoxicity in these cell lines. Although treatment with up to 100 μg/ml CAM alone had little effect on cell growth inhibition, the accumulation of autophagosomes and p62 was observed after treatment with 25 μg/ml CAM. This result indicated that CAM blocked autophagy flux. However, the combined treatment of BZ and CAM resulted in more pronounced autophagy induction, as assessed by increased expression ratios of LC3B-II to LC3B-I and clearance of intracellular p62, than treatment with BZ alone. This combination further enhanced induction of the pro-apoptotic transcription factor CHOP (CADD153) and the chaperone protein GRP78. Knockdown of CHOP by siRNA attenuated the death-promoting effect of BZ in MDA-MB-231 cells. A wild-type murine embryonic fibroblast (MEF) cell line also exhibited enhanced BZ-induced cytotoxicity with the addition of CAM, whereas a Chop knockout MEF cell line completely abolished this enhancement and exhibited resistance to BZ treatment. These data suggest that endoplasmic reticulum (ER)-stress mediated CHOP induction is involved in pronounced cytotoxicity by combining these reagents. Simultaneously targeting two major intracellular protein degradation pathways such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome pathway by CAM may improve the therapeutic outcome in breast cancer patients via ER-stress mediated apoptosis.
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影响因子：
11.2
作者：
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作者：
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