铜绿假单胞菌甘露糖敏感血凝菌毛（PA-MSHA）通过下调Nrf2/p62来抑制多柔比星耐药的MCF-7/ADR人乳腺癌细胞的生长。

PA-MSHA inhibits the growth of doxorubicin-resistant MCF-7/ADR human breast cancer cells by downregulating Nrf2/p62.

作者信息

Wei Yingze, Liu Danyang, Jin Xiaoxia, Gao Pan, Wang Qingying, Zhang Jiawen, Zhang Nong

机构信息

Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Department of Pathology, Nantong Tumor Hospital, Nantong, Jiangsu, China.

出版信息

Cancer Med. 2016 Dec;5(12):3520-3531. doi: 10.1002/cam4.938. Epub 2016 Oct 18.

DOI:10.1002/cam4.938

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5224842/

Abstract

Acquired resistance to doxorubicin in breast cancer is a serious therapeutic problem. In this study, we investigated whether Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) could inhibit the growth of doxorubicin-resistant breast cancer cells. We found that the expressions of Nrf2 and p62 in breast cancer were higher than that in the corresponding adjacent normal tissues and benign breast epithelial cell. The expressions of Nrf2 and p62 in breast cancer doxorubicin-resistant cells MCF-7/ADR were higher than that in doxorubicin-sensitive cells MCF-7. Silencing of Nrf2 or p62 rendered breast cancer cells more susceptible to doxorubicin. We further demonstrated that PA-MSHA inhibited growth and induced apoptosis of MCF-7/ADR cells but not MCF-7 cells. Subcutaneous administration of PA-MSHA greatly inhibited the growth of xenograft tumors from MCF-7/ADR cells in nude mice. In addition, PA-MSHA could downregulate Nrf2 and p62 in vitro and in vivo. These results suggested that activation of Nrf2 and p62 was associated with doxorubicin resistance in breast cancer. PA-MSHA could inhibit the growth of doxorubicin-resistant MCF-7/ADR cells and its potential mechanism might be due to the suppression of Nrf2/p62. It indicated the possibility of using PA-MSHA in doxorubicin-resistant breast cancer.

摘要

乳腺癌对多柔比星获得性耐药是一个严重的治疗问题。在本研究中，我们调查了铜绿假单胞菌甘露糖敏感血凝素（PA-MSHA）是否能抑制多柔比星耐药乳腺癌细胞的生长。我们发现，乳腺癌中Nrf2和p62的表达高于相应的相邻正常组织和乳腺良性上皮细胞。乳腺癌多柔比星耐药细胞MCF-7/ADR中Nrf2和p62的表达高于多柔比星敏感细胞MCF-7。沉默Nrf2或p62使乳腺癌细胞对多柔比星更敏感。我们进一步证明，PA-MSHA抑制MCF-7/ADR细胞的生长并诱导其凋亡，但对MCF-7细胞无此作用。皮下注射PA-MSHA可显著抑制裸鼠体内MCF-7/ADR细胞异种移植瘤的生长。此外，PA-MSHA在体外和体内均可下调Nrf2和p62。这些结果表明，Nrf2和p62的激活与乳腺癌对多柔比星的耐药有关。PA-MSHA可抑制多柔比星耐药的MCF-7/ADR细胞的生长，其潜在机制可能是抑制Nrf2/p62。这表明PA-MSHA用于治疗多柔比星耐药乳腺癌的可能性。