| RRC ID |
77533
|
| 著者 |
Nishisho T, Hata K, Nakanishi M, Morita Y, Sun-Wada GH, Wada Y, Yasui N, Yoneda T.
|
| タイトル |
The a3 isoform vacuolar type H⁺-ATPase promotes distant metastasis in the mouse B16 melanoma cells.
|
| ジャーナル |
Mol Cancer Res
|
| Abstract |
Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H(+)-ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V-ATPase in distant metastasis. Real-time PCR analysis revealed that the high-metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis.
|
| 巻・号 |
9(7)
|
| ページ |
845-55
|
| 公開日 |
2011-7-1
|
| DOI |
10.1158/1541-7786.MCR-10-0449
|
| PII |
1541-7786.MCR-10-0449
|
| PMID |
21669964
|
| MeSH |
Animals
Benzamides / pharmacology
Benzofurans / pharmacology
Bone Neoplasms / enzymology
Bone Neoplasms / secondary*
Cell Proliferation
Lung Neoplasms / enzymology
Lung Neoplasms / secondary*
Male
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Melanoma, Experimental / enzymology
Melanoma, Experimental / secondary*
Mice
Neoplasm Invasiveness
Neoplasm Metastasis
Tumor Microenvironment*
Vacuolar Proton-Translocating ATPases / metabolism*
Wound Healing / genetics
|
| IF |
4.63
|
| リソース情報 |
| ヒト・動物細胞 |
B16
B16F10(RCB2630) |
