A role for vault particles as mediator for therapeutic effects against endocrine tumors

Abstract

[08:40 – 08:50]The vault complex, consisting of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1) and small untranslated RNA molecules (vault RNAs 1 – 4), is considered the largest intracellular ribonucleoprotein particle. Although in recent years, vaults were believed to be involved in multidrug resistance (MDR), the exact function of this complex has remained unclear. Recently, we investigated the therapeutic applicability of a Tumor-Vascular-Disrupting Agent (ASA) in preclinical models for neuroendocrine tumors of the gastroenteropancreatic system (BON) and adrenocortical carcinoma (NCIh295R). Upon treatment we detected highly significant anti-tumoral effects in BON xenografts while no effects were detectable for NCI-H295R. In an attempt to explain differences in therapeutic responsiveness, gene expression patterns within these tumors was investigated by an affymetrix gene array. Subsequent analyses identified vault RNAs 1 – 3 as the most pronounced regulated transcripts. Interestingly, we detected increased vault RNA expression in the tumor model showing therapeutic responsiveness. Quantitative Real Time PCR confirmed these results for ASA treated BON tumors (% of 100% controls; vault1: 2468.1 ± 367%, p < 0.001; vault2: 1922.5 ± 235%, p < 0.001; vault3: 901.3 ± 119%, p < 0.001) while no changes were detectable for the not-responding NCI-H295R-xenografts (% of 100% controls; vault1: 224.1 ± 84%, p > 0.05; vault2: 113 ± 23% p > 0.05; vault3: 89 ± 14% p > 0.05). Subsequently, we investigated NCI-H295R-xenografts which had been treated with two different chemotherapeutic regimens (EDP-M and LEDP-M). In this therapeutic setting treatment-dependent upregulation of vault RNAs could also be detected in NCI-H295R-tumors (% of 100% controls; vault1: EDP-M 296.3 ± 44%, p < 0.001; LEDP-M 243.5 ± 16%, p < 0.001; vault2: EDP-M 157.2 ± 20%, p > 0.05; LEDP-M 160.7 ± 20%, p > 0.05; vault3: EDP-M 241.2 ± 55%, p < 0.001; LEDP-M 118.9 ± 16%, p > 0.05). Further in vitro analyses revealed dynamic changes in vault RNA expression also upon blasticidin, doxorubicin, mitotane treatment and a significant increase in MVP protein levels upon TNF alpha treatment in BON cells. In summary, further investigation and manipulation of vault particles might have potential to improve efficacy of anticancer drugs in endocrine tumors.