The naturally occurring polyphenol, curcumin, has been shown to be a potent chemotherapeutic agent in a variety of tumor models;however, its effects on tumor-associated immunosuppression have not been investigated to any great extent. The accumulation of immature myeloid cells is a hallmark of cancer and our data indicate that exosomes produced by tumors can suppress the differentiation of immature myeloid cells (iMCs). We have now found that curcumin treatment inhibits the tumor exosome-mediated suppression of differentiation of IMCs in mice, preventing their accumulation in the spleen and delaying tumor growth. Analysis of the composition of the tumor exosomes using a proteomics approach identified CSN5 as a candidate regulatory molecule and siRNA knockdown of CSN5 resulted in attenuation of the tumor exosome- mediated induction of IMCs in the spleen, suggesting that exosomal CSN5 plays a key role in tumor exosome-mediated immune suppression. We have now found that curcumin treatment destabilizes exosomal CSN5. The exosomal CSN5 is stable when associated with phosphorylated STAM1. Curcumin treatment leads to the dephosphorylation of STAM1 permitting the recruitment of an E3 ligase BARD1/BRCA1 to the CSN5 complex, resulting in CSN5 degradation. Our in vitro kinase assay results indicate that the curcumin- mediated disassociation of STAM1 from CSN5 complex is most likely due to the inhibition of CSN5- associated kinase activity. The clinical relevance of these studies is supported by our recent data that indicate that CSN5 is packed in exosomes isolated from the peripheral blood of breast cancer patients but not healthy subjects. We propose: (1) To use siRNA technology to determine if tumor exosomal CSN5 is a primary target of curcumin in its prevention of breast tumor exosome-mediated immunosuppression;(2) To determine whether CSN5-associated kinase activity prevents BARD1/BRCA1 E3 complex degradation of CSN5 in TS/A tumor cells;and (3) To determine whether curcumin treatment of human tumor cells results in degradation of CSN5 and prevents blocking of differentiation of CD33 (equivalent to mouse GDI lb+) Grl+ cells. We will further determine if exosomes packed with CSN5 circulate in the peripheral blood of patients with breast cancer and if overproduction of exosomes is correlated with the accumulation of iMCs in patients with breast cancer.
The data generated should identify a novel mechanism for the actions of curcumin and identify its molecular targets in preventing CSN5/tumor exosome-mediated blockade of myeloid cell differentiation.
|Zhuang, Xiaoying; Teng, Yun; Samykutty, Abhilash et al. (2016) Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression. Mol Ther 24:96-105|
|Deng, Zhongbin; Mu, Jingyao; Tseng, Michael et al. (2015) Enterobacteria-secreted particles induce production of exosome-like S1P-containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis. Nat Commun 6:6956|
|Wang, Qilong; Ren, Yi; Mu, Jingyao et al. (2015) Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites. Cancer Res 75:2520-9|
|Zhuang, Xiaoying; Deng, Zhong-Bin; Mu, Jingyao et al. (2015) Ginger-derived nanoparticles protect against alcohol-induced liver damage. J Extracell Vesicles 4:28713|
|Mu, Jingyao; Zhuang, Xiaoying; Wang, Qilong et al. (2014) Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol Nutr Food Res 58:1561-73|
|Zhang, Huang-Ge; Grizzle, William E (2014) Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol 184:28-41|
|Jiang, Hong; Wang, Ping; Li, Xiaohua et al. (2014) Restoration of miR17/20a in solid tumor cells enhances the natural killer cell antitumor activity by targeting Mekk2. Cancer Immunol Res 2:789-99|
|Wang, Baomei; Zhuang, Xiaoying; Deng, Zhong-Bin et al. (2014) Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. Mol Ther 22:522-534|
|Deng, Zhong-Bin; Zhuang, Xiaoying; Ju, Songwen et al. (2013) Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells. J Immunol 190:3579-89|
|Wang, Qilong; Zhuang, Xiaoying; Mu, Jingyao et al. (2013) Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat Commun 4:1867|
Showing the most recent 10 out of 23 publications