Lipopolysaccharide sensitizes the therapeutic response of breast cancer to IAP antagonist

by Selleckchem | Apr 03 2023

Inhibitor of apoptosis protein (IAP) is a class of E3 ubiquitin ligases functioning to support cancer survival and growth. Many small-molecule IAP antagonists have been developed, aiming to degrade IAP proteins to kill cancer. We have evaluated the effect of lipopolysaccharide (LPS), a component of the bacterial outer membrane, on IAP antagonists in treating breast cancer in a mouse model to guide future clinical trials. We show that LPS promotes IAP antagonist-induced regression of triple-negative breast cancer (TNBC) from MDA-MB-231 cells in immunodeficient mice. IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. The apoptosis caused by LPS plus SM-164 is blocked by toll-like receptor 4 (TLR4) or MyD88 inhibitor, which inhibits LPS-induced TNFα production by the cancer cells. Consistent with this, MDA-MB-231 cell apoptosis induced by LPS plus SM-164 is also blocked by the TNF inhibitor. LPS alone does not kill MDA-MB-231 cells because it markedly increases the protein level of cIAP1/2, which is directly associated with and stabilized by MyD88, an adaptor protein of TLR4. ER+ MCF7 breast cancer cells expressing low levels of cIAP1/2 undergo apoptosis in response to SM-164 combined with TNFα but not with LPS. Furthermore, TNFα but not LPS alone inhibits MCF7 cell growth in vitro. Consistent with these, LPS combined with SM-164, but not either of them alone, causes regression of ER+ breast cancer from MCF7 cells in immunodeficient mice. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER+ breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy.

Comments：

The study suggests that lipopolysaccharide (LPS), a component of the bacterial outer membrane, can enhance the therapeutic effect of IAP antagonists in treating triple-negative and ER+ breast cancer in mice by inducing rapid apoptosis of cancer cells through TLR4- and MyD88-mediated production of TNFα. The IAP antagonists tested, including SM-164, AT-406, and BV6, did not kill cancer cells alone but allowed LPS to trigger cancer cell apoptosis.

The study also found that LPS increased the protein level of cIAP1/2, which is associated with and stabilized by MyD88, an adaptor protein of TLR4. This explains why LPS alone did not kill MDA-MB-231 cells, but instead, it sensitized them to IAP antagonists by increasing TNFα production.

In contrast, ER+ MCF7 breast cancer cells expressing low levels of cIAP1/2 underwent apoptosis in response to SM-164 combined with TNFα but not with LPS. TNFα but not LPS alone inhibited MCF7 cell growth in vitro. Consistent with these findings, LPS combined with SM-164, but not either of them alone, caused regression of ER+ breast cancer from MCF7 cells in immunodeficient mice.

The study concludes that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy, as LPS plays a critical role in sensitizing cancer cells to IAP antagonist-induced apoptosis. These findings suggest a potential strategy to improve the therapeutic response of breast cancer to IAP antagonists in clinical trials.