Vault Particles in Cancer Progression, Multidrug Resistance, and Drug Delivery: Current Insights and Future Applications

Abstract

Vault particles (VPs) are highly conserved large ribonucleoprotein complexes found exclusively in eukaryotes. They play critical roles in various cellular processes, but their involvement in cancer progression and multidrug resistance (MDR) is the most extensively studied. VPs are composed of the major vault protein (MVP), vault RNAs (vtRNAs), vault poly (ADP-ribose) polymerase, and telomerase-associated protein-1. These components are involved in the regulation of signaling pathways that affect tumor survival, proliferation, and metastasis. MVP has been associated with aggressive tumor phenotypes, while vtRNAs modulate cell proliferation, apoptosis, and autophagy. VPs also contribute to MDR by sequestering chemotherapeutic agents, altering their accumulation in the nucleus, and regulating lysosomal dynamics. Furthermore, small vault RNA-derived fragments participate in gene silencing and intercellular communication, reinforcing the role of precursors of vtRNAs in cancer development. Beyond their biological roles, VPs present a promising platform for drug delivery, due to their unique ability to encapsulate a wide range of biomolecules and therapeutic agents, followed by controlled release. This review compiles data from PubMed and Scopus, with a literature search conducted up until December 2024, highlighting current knowledge regarding VPs and their crucial involvement in cancer-related mechanisms and their applications in overcoming cancer drug resistance.

Keywords: cancer progression; drug delivery nanoparticle; major vault protein (MVP); multidrug resistance (MDR); small vault RNA (svtRNA); vault RNA (vtRNAs); vault particle (VP).

Figure 1

Architectural characteristics of vault particles (VPs) and their opening mechanism. (a) A cross-sectional view featuring a schematic illustration and the positioning of the VP’s components. The outer shell of the mammalian VP is composed of 78 copies of major vault protein (MVP), which assembles into a large internal cavity that houses vault RNAs (vtRNAs), vault poly (ADP-ribose) polymerase (vPARP), and telomerase-associated protein-1 (TEP1). vtRNAs are occupied at the edge of the particle. TEP1 interacts directly with vtRNAs, and it is essential for their incorporation inside the particle. Meanwhile, vPARP binds internally to the MVP, stabilizing the whole particle, (b) VP can encapsulate and release its cargo under specific conditions. In vitro experiments have shown that at pH < 7 and at a temperature above 60 °C, the VP rapidly opens into two halves and releases its delivery.

Figure 2

Predicted secondary structures of the four human vault RNAs (vtRNAs), on the left, and the sole mouse vtRNA, on the right, using RNAFold.

Figure 3

Sequence alignment of the four human vault RNAs (vtRNAs) and the sole mouse vtRNA. The alignment was performed using Clustal Omega and Jalview 2.11.1.7 was used for illustration purposes. For the alignment, the highly conserved nucleotides (100%) are indicated by dark blue color, the moderately conserved nucleotides (80%) are indicated with blue color, and the less conserved nucleotides (60%) are indicated with light blue color. It also illustrated the Pol III type 2 promoter, with two internal promoter sequences, the A box, and B box, which facilitate binding with the transcription factors TFIIIC and TFIIIB, like the mechanism in tRNAs. Alignment numbering does not correspond to the numbering of the respective vtRNAs.

Figure 4

Mechanisms underlying vault-mediated drug resistance. Drugs can (1) be transported out of the nucleus, (2) or encapsulated inside vault particles and pass through nuclear pores, (3) accumulate within cytosolic vesicles, (4) undergo exocytosis, (5) become sequestered within lysosomes or (6) can be trapped by directly binding to vtRNAs like mitoxantrone.

Figure 5

Potential strategies targeting major vault protein (MVP) and vault RNAs (vtRNAs). The MVP gene can be knocked out using the CRISPR/Cas9 genome editing system or can be knocked down through RNA interference (siRNA). Additionally, MVP may be targeted by small molecule inhibitors or specific anti-MVP antibodies. These approaches can lead to the downregulation of key cancer signaling pathways, such as PI3K/AKT/mTOR and MAPK/ERK, thereby inhibiting cancer cell proliferation, survival, and migration. Targeting MVP can induce the disassembly of vault particles, allowing therapeutic agents to penetrate and act more effectively within the cell. Similarly, knocking out or knocking down vault RNAs can impair cancer cell proliferation and enhance the accumulation of chemotherapeutic drugs in the cytoplasm, potentially improving treatment efficacy.