Lipopolysaccharide sensitizes the therapeutic response of breast cancer to IAP antagonist

• Published in: Frontiers in immunology Vol. 13; p. 906357
• Main Authors: Liu, Xin, Yao, Jimmy J., Chen, Zhongxuan, Lei, Wei, Duan, Rong, Yao, Zhenqiang
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 31-08-2022
• Subjects: apoptosis; breast cancer; Immunology; lipopolysaccharide; MyD88; TNF-α; Tolllike receptor 4
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.906357

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.