Reversal of LRP-associated drug resistance in colon carcinoma sw-620 cells

Kitazono, Masaki; Okumura, Hiroshi; Ikeda, Ryuji; Sumizawa, Tomoyuki; Furukawa, Tatsuhiko; Nagayama, Shuichi; Seto, K.; Aikou, Takashi; Akiyama, Shin-ichi

doi:10.1002/1097-0215(20010101)91:1<126::aid-ijc1018>3.0.co;2-8

Cited by 64 publications

(57 citation statements)

References 19 publications

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“…Although the sensitization of cell lines to antineoplastic drugs through MVP depletion has been shown (18,19) and large amount of patient data point to a vital role for MVP in drug resistance (2,3,16), it is far from certain that this protein plays an essential role in chemosensitivity of human cancer. Indeed, it has been reported that MVP overexpression, or depletion, does not affect drug sensitivity nor intracellular sequestration (7, 42 -44).…”

Section: Discussionmentioning

confidence: 99%

“…In studies where a colon carcinoma cell line was chemically induced to differentiate, Kitazono et al (18,19) have shown a direct correlation between MVP levels and progressive resistance to doxorubicin. In this model, MVPdependent resistance did not increase cellular efflux of doxorubicin but was associated with a subcellular redistribution of the drug away from the nucleus.…”

Section: Introductionmentioning

confidence: 99%

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Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Herlevsen

Oxford

Owens

et al. 2007

Molecular Cancer Therapeutics

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The major vault protein (MVP) is the major constituent of the vault particle, the largest known ribonuclear protein complex. To date, vaults have no clear function, although their low expression levels in de novo chemosensitive and curable tumors, such as testicular cancer, make them attractive candidates as contributors to intrinsic drug resistance. Here, we show that MVP knockdown in human bladder cancer cells via small interfering RNA results in sensitization toward doxorubicin in two distinct exposure protocols. The drug was detected in the nucleus immediately following addition and was subsequently sequestered to lysosomes, predominantly located adjacent to the nucleus. MVP knockdown leads to increased sensitivity toward doxorubicin and an enhanced nuclear accumulation of the drug as well as a loss of its perinuclear sequestration. Not only doxorubicin subcellular distribution was perturbed by MVP knockdown but lysosomal markers, such as pH-sensitive LysoSensor, pinocytosed dextran conjugates after 24-h chase period, and the lysosomal specific antigen Lamp-1, also showed a markedly different staining compared with controls. Lysosomes appeared dispersed through the cytoplasm without a clear organization adjacent to the nucleus. Microtubules, however, appeared unperturbed in cells with reduced MVP expression. Based on these data, we hypothesize that MVP and, by extension, vault complexes are important for lysosomal function and may influence cellular drug resistance by virtue of this role. [Mol Cancer Ther 2007;6(6):1804 -13]

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Herlevsen

Oxford

Owens

et al. 2007

Molecular Cancer Therapeutics

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“…Nevertheless, a small part (~5%) of major vault protein (MVP) is consistently associated with the nucleus (Abbondanza et al, 1998;Chugani et al, 1993). Although the cellular function of vaults is still unknown, their subcellular localization and distinct morphology point to a role for vaults in intracellular, particularly nucleo-cytoplasmic, transport (Abbondanza et al, 1998;Chugani et al, 1993;Hamill and Suprenant, 1997;Herrmann et al, 1999;Herrmann et al, 1996;Kitazono et al, 2001;Kitazono et al, 1999;Li et al, 1999). Vaults are frequently upregulated in multidrug-resistant cell lines and tumors of different histogenetic origin.…”

Section: Introductionmentioning

confidence: 99%

The formation of vault-tubes: a dynamic interaction between vaults and vault PARP

Zon

Mossink

Schoester

et al. 2003

Journal of Cell Science

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tube-like structures in the cytoplasm. Raising the temperature could reverse this process. When the vaulttubes were formed, there were fewer or no VPARP-rods present in the cytoplasm, suggesting an incorporation of the VPARP into the vault-tubes. MVP molecules have to interact with each other via their coiled-coil domain in order to form vault-tubes. Furthermore, the stability of microtubules influenced the efficiency of vault-tube formation at 21°C. The dynamics and structure of the tubes were examined using confocal microscopy. Our data indicate a direct and dynamic relationship between vaults and VPARP, providing further clues to unravel the function of vaults.

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“…Furthermore, it was shown in several MDR cell lines that not only MVP was up-regulated but other vault components as well (13,14). The most compelling data that link vaults to MDR comes from Kitazono et al (15,16). They used MVP-specific ribozymes in SW620 cells, which were induced by sodium butyrate to overexpress MVP.…”

mentioning

confidence: 99%

Multiple Human Vault RNAs

Zon¹,

Mossink²,

Schoester³

et al. 2001

Journal of Biological Chemistry

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Human vaults are intracellular ribonucleoprotein particles believed to be involved in multidrug resistance. The complex consists of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1), and several small untranslated RNA molecules. Three human vault RNA genes (HVG1-3) have been described, and a fourth was found in a homology search (HVG4). In the literature only the association of hvg1 with vaults was shown in vivo. However, in a yeast three-hybrid screen the association of hvg1, hvg2, and hvg4 with TEP1 was demonstrated. In this study we investigated the expression and vault association of different vault RNAs in a variety of cell lines, including pairs of drugsensitive and drug-resistant cells. HVG1-3 are expressed in all cell lines examined, however, none of the cell lines expressed HVG4. This probably is a consequence of the absence of essential external polymerase III promoter elements. The bulk of the vault RNA associated with vaults was hvg1. Interestingly, an increased amount of hvg3 was bound to vaults isolated from multidrug-resistant cell lines. Our findings suggest that vaults bind the RNA molecules with different affinities in different situations. The ratio in which the vault RNAs are associated with vaults might be of functional importance.

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Reversal of LRP-associated drug resistance in colon carcinoma sw-620 cells

Cited by 64 publications

References 19 publications

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

The formation of vault-tubes: a dynamic interaction between vaults and vault PARP

Multiple Human Vault RNAs

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