BROAD DISTRIBUTION OF THE MULTIDRUG RESISTANCE-RELATED VAULT LUNG RESISTANCE PROTEIN IN NORMAL HUMAN TISSUES AND TUMORS

Multidrug resistance (MDR) to anticancer drugs is a major cause of tre atment failure in cancer. The lung resistance protein LRP is a newly d escribed protein related to MDR in several in vitro models. LRP has be en shown to be a strong predictor of poor response to chemotherapy and prognosis in acute myeloid leukemia and in ovarian carcinoma patients . Recently, based on a 57% and 88% amino acid identity with major vaul t proteins from Dictyostelium discoideum and Rattus norvegicus, respec tively, we identified LRP as the human major vault protein the main co mponent of highly conserved cellular organelles named vaults. We have studied the immunohistochemical expression of LRP in the freshly froze n normal human tissues and 174 cancer specimens of 28 tumor types. LRP was broadly distributed in normal and malignant cells, but distinct p atterns of expression were noticed. High LRP expression was seen in br onchus, digestive tract, renal proximal tubules, keratinocytes, macrop hages, and adrenal cortex, whereas varying levels were observed in oth er organs LRP was detected in all tumor types examined, but its freque ncy varied, fairly reflecting the chemosensitivity of different cancer s For example, low rates of LRP positivity were seen in testicular can cer, neuroblastoma, and acute myeloid leukemia; intermediate in ovaria n cancer; and high in colon, renal, and pancreatic carcinomas. The wid e occurrence of LRP in normal and transformed cells in humans, its sim ilar distribution to that of vaults in other species, as well as the h igh level of conservation among eukaryotic cells of both the amino aci d sequence of the major vault protein and the composition and structur e of vaults, suggest that vault function is important to eukaryotic ce lls.