Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231
Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231
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DOI：
10.1158/0008-5472.can-06-3184
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Philp, Nancy J.
中科院分区：
文献类型：
--
作者：
Gallagher, Shannon M.;Castorino, John J.;Philp, Nancy J.
转移性癌细胞通过糖酵解增加葡萄糖消耗和代谢，产生大量乳酸。最近的研究表明，乳酸外排是由单羧酸转运蛋白（MCT）介导的，它由一个催化单元（MCT）和一个辅助亚基（CD 147）组成，包括功能性乳酸转运蛋白。CD 147是一种细胞外基质金属蛋白酶（MMP）诱导剂，在转移性癌细胞中高度表达。由于有氧糖酵解是转移性癌症的标志，我们研究了CD 147表达的增加是否与MDA-MB-231（一种高转移性乳腺癌细胞系）中的MCT表达有关。与正常乳腺组织来源的细胞相比，MDA-MB-231细胞中MCT 4 mRNA和蛋白表达增加。MCT 4与CD 147共定位于质膜和从细胞表面脱落的膜泡中。小干扰RNA介导的MCT 4沉默损害了CD 147的成熟和向细胞表面的运输，导致CD 147在内质网中积累。沉默MCT 4还导致膜泡减少和MDA-MB-231细胞体外迁移减少。CD 147的敲低导致质膜中MCT 4的丢失和内溶酶体中转运蛋白的蓄积。这些研究首次证实转移性癌细胞中CD 147表达的增加与MCT 4的上调相关。MCT/CD 147复合物的协同活性可通过CD 147介导的MMP诱导和乳酸盐刺激的血管生成和透明质酸产生促进肿瘤细胞的迁移。这些数据提供了转移性癌症的两个标志之间的分子联系：糖酵解开关和CD 147表达增加。
Metastatic cancer cells increase glucose consumption and metabolism via glycolysis, producing large quantities of lactate. Recent work has shown that lactate efflux is mediated by monocarboxylate transporters (MCT), which are composed of a catalytic unit (MCT) and an accessory subunit (CD147), comprising the functional lactate transporter. CD147, an extracellular matrix metalloproteinase (MMP) inducer, is highly expressed in metastatic cancer cells. Because aerobic glycolysis is a hallmark of metastatic cancer, we examined whether increases in CD147 expression were linked to MCT expression in MDA-MB-231, a highly metastatic breast cancer cell line. MCT4 mRNA and protein expression were increased in MDA-MB-231 cells compared with cells derived from normal mammary tissue. MCT4 colocalized with CD147 in the plasma membrane and in membrane blebs shed from the cell surface. Small interfering RNA-mediated silencing of MCT4 impaired the maturation and trafficking of CD147 to the cell surface, resulting in accumulation of CD147 in the endoplasmic reticulum. Silencing MCT4 also resulted in fewer membrane blebs and decreased migration of MDA-MB-231 cells in vitro. Knockdown of CD147 resulted in loss of MCT4 in the plasma membrane and accumulation of the transporter in endolysosomes. These studies establish for the first time that increased expression of CD147 in metastatic cancer cells is coupled to the up-regulation of MCT4. The synergistic activities of the MCT/CD147 complex could facilitate migration of tumor cells by CD147-mediated MMP induction and lactate-stimulated angiogenesis and hyaluronan production. These data provide a molecular link between two hallmarks of metastatic cancer: the glycolytic switch and increased expression of CD147.