Tumor cells that are insensitive to anticancer drugs frequently have a multidrug-resistant (MDR) phenotype. Proteins that can be involved in this phenomenon are transport-associated proteins such as P-glycoprotein, multidrug-resistance protein 1, breast cancer resistance protein, and lung resistance-related protein (LRP). LRP was identified as the major vault protein (MVP), the main component of multimeric vault particles. With the recent identification of the two minor vault proteins as telomerase-associated protein (TEP1) and vault-poly (ADP-ribose) polymerase (VPARP), and with high-resolution three-dimensional imaging, the composition of vaults is almost unraveled. Although the first direct evidence for a causal relationship between LRP/MVP expression and drug resistance has been obtained, many functional aspects of vaults in normal physiology and in MDR still need to be clarified. The current clinical data on LRP/MVP detection indicate that LRP/MVP expression can be of high clinical value to predict the response to chemotherapy of several tumor types.

P-glycoprotein (Pgp) and vaults are associated with multidrug resistance in tumor cells, but their physiological functions are not yet clear. Pgp, the prototypical transmembrane transporter molecule, may also facilitate the migration of skin dendritic cells (DC). Vaults—ribonucleoprotein cell organelles, frequently overexpressed in Pgp-negative drug-resistant tumor cells—have also been associated with intracellular transport processes. Given the pivotal role of DC in dealing with exposure to potentially harmful substances, the present study was set out to examine the expression of Pgp and vaults during differentiation and maturation of DC. DC were obtained from different sources, including blood-derived monocytes, CD34+ mononuclear cells, and chronic myeloid leukemia cells. Whereas flow cytometric and immunocytochemical analyses showed slightly augmented levels of Pgp, up-regulation of vault expression during DC culturing was strong, readily confirmed by Western blotting, and independent of the source of DC. In further exploring the functional significance of vault expression, it was found that supplementing DC cultures with polyclonal or mAbs against the major vault protein led to lower viabilities of LPS- or TNF-α-matured monocytes-DC. Moreover, expression of critical differentiation, maturation, and costimulatory molecules, including CD1a and CD83, was reduced and their capacity to induce Ag-specific T cell proliferative and IFN-γ release responses was impaired. These data point to a role for vaults in both DC survival and functioning as APC.

No abstract

Aim-To analyse the expression of multidrug resistance (MDR) related proteins at diVerent steps in colorectal carcinogenesis. Methods-The presence of three MDR related proteins (Pgp, MRP1, and LRP/ MVP) was studied by means of immunohistochemistry in normal, adenomatous, and malignant colorectal epithelium. Formaldehyde fixed, paraYn embedded tissue sections of 17 samples of colorectal tissue were used (normal mucosa, n= 4; adjacent mucosa, n= 5; adenoma, n = 5; carcinoma, n = 3). Results-For all three proteins, expression was found in the surface epithelium and the upper parts of the crypts in normal colon. In the adenomas, staining was seen along the complete length of the crypts. In the carcinomas analysed, all epithelium showed positive staining. Mucosa adjacent to either carcinoma or adenoma showed staining patterns mostly resembling those of normal mucosa, but sometimes some extension of staining was seen along the crypt. Conclusions-These proteins already show increased expression in the adenoma stage. In the absence of adequate mucin production in adenomas, MDR related proteins could be an important factor in protecting the epithelium against further environmentally induced genetic damage. This could be one of the reasons why only about 5% of colorectal adenomas will actually progress to carcinomas. (J Clin Pathol 1999;52:450-454)

M ultidrug resistance (MDR) is the major cause of chemotherapeutic failure in cancer treatment (Lehnert 1996). Several mechanisms are responsible for mediating MDR, including the overexpression of transmembrane transporter molecules, such as P-glycoprotein (reviewed in Germann 1996), multidrug resistance protein (MRP) 1, MRP2, MRP3 (reviewed in Borst et al. 1999), and breast cancer resistance protein (reviewed in Doyle et al. 1998), which act as drug efflux pumps, decreasing intracellular drug accumulation. In clinical drug resistance, however, other mechanisms may play a role, e.g., drug sequestration into exocytotic vesicles. Evidence has been obtained that subcellular particles called vaults may play a critical role in such a mechanism (Kedersha and Rome 1986;Scheffer et al. 1995). Vaults are evolutionarily highly conserved large ribonucleoprotein particles (Kedersha et al. 1990). The particles represent multimeric RNAprotein complexes with one predominant member, the major vault protein (MVP). The bulk of vaults is present in the cytoplasm. In addition, based on MVP immunolocalization in cells and tissues, a small fraction of vaults appear to be localized at or near the nuclear membrane and the nuclear pore complex (Chugani et al. 1993). Although the cellular role of the vault particle has remained elusive, several findings support the notion that vaults have a transport function, acting as a carrier, mediating bidirectional nucleo-cytoplasmic exchange, and vesicular transport of compounds, including cytostatic drugs (Rome et al. 1991;Chugani et al. 1993;Herrmann et al. 1996Herrmann et al. , 1999Hamill and Suprenant 1997;Abbondanza et al. 1998;Kong et al. 1999). Recently, Kitazono et al. (1999) demonstrated, using an LRP-induction system and LRP -specific ribozymes, that LRP is involved in resistance to doxorubicin, vincristine, VP-16, taxol, and gramicidine-D, and has an important role in the transport of doxorubicin between the nucleus and the cytoplasm in the SW-620 human colon carcinoma cell line.