Abstract
Cancer cells show significant dysregulation of genes expression, which may favor their survival in the tumor environment. In this study, the cellular vault’s components MVP (major vault protein), TEP1 (telomerase-associated protein 1) and vPARP (vault poly(ADP-ribose) polymerase) were transiently or completely inhibited in U2OS cells (human bone osteosarcoma epithelial cells) to evaluate their impact on the cell proliferative and migratory capacity as well as on the development of their resistance to the drug vinorelbine. Comparative analysis of MVP protein expression level in normal colon tissue, primary colorectal tumor, and metastasis showed that the expression of this protein does not increase significantly in the primary tumor, but its expression increases in metastatic cells. Further comparative molecular analysis using the whole transcriptome microarrays for MVP-positive and MVP-negative cells showed that MVP is involved in regulating proliferation and migration of cancer cells. MVP may facilitate metastasis of colon cancer due to its impact on cell migration. Moreover, two vault proteins, MVP and TEP1, contribute the resistance to vinorelbine, while vPARP does not.
Highlights
Cellular vaults are cytoplasmic ribonucleoprotein structures with a still unclear role in the cell, their participation in the development of drug resistance in cancer cells has already been demonstrated [1,2]
Tissue samples from 54 patients with colorectal cancer were included for the comparative analysis of the expression in normal tissue vs. primary tumor, and tissue samples from 57 patients to compare expression in primary tumor vs. lymph node metastasis
MVP causes a rescue effect and Akt is phosphorylated (S473) (Figure 6D). Both the MVP protein and whole vaults have been studied for many years, but their real function in the cell has not been fully confirmed
Summary
Cellular vaults are cytoplasmic ribonucleoprotein structures with a still unclear role in the cell, their participation in the development of drug resistance in cancer cells has already been demonstrated [1,2]. Being approximately 1:8 [10] excludes the possibility of all these components forming a molecule with 39-fold symmetry revealed in the crystal structure [8] This indicates that the TEP1 and vPARP bind only to a certain fraction of vaults. The discovery mentioned above where it was found that MVP is the same protein as LRP, opened a discussion on the role of the MVP protein and whole vaults in the mechanism of multidrug resistance in different types of cancers (see reviews [1,11,12]). We reached for the first time an important observation that MVP increases in metastatic cancer cells This observation opens a new direction of research, showing the new role of MVP, and probably vaults, in the processes responsible for the formation of metastasis. Total inhibition of MVP expression in certain cancer cell types (HAP1) resulted in the death of the cells’ population
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