LAUSR

BACKGROUND: Mortalin/GRP-75(mt-hsp70, HSPA9) is a mitochondrial chaperone protein, also found in the cytoplasm, endoplasmic reticulum and cytoplasmic vesicles. It functions in many cellular processes such as mitochondrial biogenesis, intracellular trafficking, cell proliferation, signaling, immortalization and tumorigenesis, Thus, inhibition of mortalin is a promising avenue for cancer therapy. Previous studies in our lab have suggested that mortalin contributes to breast cancer development and progression. We showed tumor exosome secretion was decreased by knockdown of mortalin expression using HIV-1 Nef peptides. Specifically, these peptides can block exosome secretion and also mediate cell cycle arrest in MDA-MB-231 and MCF-7 breast cancer cells. AIMS: This study aims to investigate further the function and mechanism of interaction of PEG- SMR-CLU peptide and SMR-CPP peptide, and chaperone mortalin and to explore the effect of SMR-derived peptides and mortalin on human breast cancer and leukemia cell lines. RESULTS: Our results demonstrate that the modified SMRwt peptides not only affect breast cancer cell proliferation and arrest breast cancer cell growth, but they also inhibit migration of breast cancer cells. SMRwt peptides also block exosome-mediated release of complement, and allow the cells to die via complement induced cell death, and reduced mortalin protein expression. We further determined that expression levels of the mesenchymal markers vimentin (VIM) was decreased in presence of SMRwt peptides and MKT-077. CONCLUSIONS: Mortalin may promote cell proliferation and invasion via induction of epithelial mesenchymal transition (EMT) of cancer cells, which has a potential therapeutic target in cancer immunotherapy. SMRwt peptides block tumor exosome release and reduce the expression of mortalin. This may be a means to decreases breast cancer cell invasion and metastasis, which may have important clinical applications for late stage breast cancer chemotherapy. Furthermore, SMRwt peptides and inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and is associated with a diminished EMT. These findings support a role for SMR peptide and mortalin in the induction of EMT, prompting a further investigation into their therapeutic value in cancer metastasis. Citation Format: Ming B. Huang, Vinvent C. Bond. Role of Nef secretion modification region (SMR) peptides and the chaperone mortalin in breast cancer and leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1869.