Researchers at the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College report that the pseudokinase Tribble 3 (TRIB3), a stress sensor in response to various tumor microenvironments or niche rich stressors, play a vital role to support breast cancer stemness. The findings,published on Dec. 16, 2019 Online of Nature Communications, suggest TRIB3 supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L.
The work by principal investigator Bing Cui, PhD, and Zhuowei Hu, MD, PhD and colleagues found that various stressors such as chronic inflammation, hypoxia, and glucose deficiency in the tumor microenvironment can enhance the stemness of breast tumors through TRIB3. The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. In this study, the researchers demonstrated that elevated expression of TRIB3 is positively associated with the poor prognosis of breast cancer patients. Moreover, the expression of TRIB3 is higher in the cancer stem cell (CSCs) population than in the non-CSCs population. The in vitro mammosphere formation, in vivo tumor formation, and molecular pharmacological experiments confirmed the following findings. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes the transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which activates FOXO1 transcription and forms a positive regulatory loop. Under the coordination of FOXO1 and SOX2, breast cancer with high TRIB3 expression shows higher tumor initiation capacity. Using tumor cell lines, primary tumors derived from spontaneous breast cancer mice and patient-derived xenografted (PDX) mice, this study also verified that interrupting the TRIB3/AKT1 interaction by a modified -helix peptide, Pep2–Ae, accelerated FOXO1 degradation, reduced SOX2 accumulation, and decreased the tumor-initiating capacity in MMTV-PyMT- and PDX mice. This research focuses on the molecular mechanism of tumor microenvironment promoting cancer stemness through stress sensor TRIB3, which provides a proof-of-concept for directly targeting BCSCs against breast cancer with high TRIB3 expression.
Fig1 High TRIB3 expression inhibits FOXO1/AKT interaction，leads to the nuclear accumulation of FOXO1 and SOX2，enhances tumor stemness and accelerates tumor progression.
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Original link: https://www.nature.com/articles/s41467-019-13700-6
