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

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.