Lipopolysaccharide sensitizes the therapeutic response of breast cancer to IAP antagonist.

Abstract

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.

• Authors: Xin Liu, Jimmy J Yao, Zhongxuan Chen, Wei Lei, Rong Duan, Zhenqiang Yao
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 906357 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 36119107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2022 Liu, Yao, Chen, Lei, Duan and Yao.

Chemical References

• Anti-Bacterial Agents
• Inhibitor of Apoptosis Proteins
• Lipopolysaccharides
• Myeloid Differentiation Factor 88
• Toll-Like Receptor 4
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factor-alpha
• Ubiquitins

Topics

• Animals
• Anti-Bacterial Agents
• Inhibitor of Apoptosis Proteins
• Lipopolysaccharides
• Mice
• Myeloid Differentiation Factor 88 (metabolism)
• Neoplasms
• Toll-Like Receptor 4 (metabolism)
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factor-alpha (metabolism)
• Ubiquitins (metabolism)