Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells

Abstract

Interactions of hyaluronan with CD44 in tumor cells play important cooperative roles in various aspects of malignancy and drug resistance. Emmprin (CD147; basigin)is a cell surface glycoprotein of the immunoglobulin superfamily that is highly up-regulated in malignant cancer cells and stimulates hyaluronan production, as well as several downstream signaling pathways. Emmprin also interacts with various monocarboxylate transporters (MCT). Malignant cancer cells use the glycolytic pathway and require MCTs to efflux lactate that results from glycolysis. Glycolysis and lactate secretion contribute to malignant cell behaviors and drug resistance in tumor cells. In the present study, we find that perturbation of endogenous hyaluronan, using small hyaluronan oligosaccharides, rapidly inhibits lactate efflux from breast carcinoma cells; down-regulation of emmprin, using emmprin small interfering RNA, also results in decreased efflux. In addition, we find that CD44 coimmunoprecipitates with MCT1, MCT4, and emmprin and colocalizes with these proteins at the plasma membrane. Moreover, after treatment of the cells with hyaluronan oligosaccharides, CD44, MCT1, and MCT4 become localized intracellularly whereas emmprin remains at the cell membrane. Together, these data indicate that constitutive interactions among hyaluronan, CD44, and emmprin contribute to regulation of MCT localization and function in the plasma membrane of breast carcinoma cells.

Inhibition of CD147 expression by RNA interference reduces proliferation, invasion and increases chemosensitivity in cancer stem cell-like HT-29 cells

“…Our flow cytometry results showed much higher expression level of CD147 in CSC-like cells than in NCSCs. Hao et al and Slomiany et al studied CD147 and CD44 expression levels in breast CSCs and found both CD147 and CD44 enriched in CSCs (37)(38)(39). Similar results were observed in our studies.…”

Kinetics of hyperpolarized 13 C 1 -pyruvate transport and metabolism in living human breast cancer cells

“…MCT1 has been shown to be elevated in a variety of cancers including in MCF7 and MDA-MB-231 human breast cancer cells (30); as shown in Fig. S2, this is also the case for T47D cells.…”

Regulation of invadopodia formation and activity by CD147

“…Though the mechanisms are not fully understood, earlier reports have demonstrated that CD147 interacts with actin (Schlosshauer et al, 1995) and that manipulation of CD147 expression results in reorganization of the actin cytoskeleton (Qian et al, 2008) and formation of actin-rich lamellipodia in Drosophila cells (Curtin et al, 2005); whether these findings are related to the mechanism of invadopodia formation is not known. In addition to its interactions with the actin cytoskeleton, CD147 interacts with several other invadopodia-enriched molecules, such as integrins (Berditchevski et al, 1997) and CD44 (Slomiany et al, 2009), that mediate attachment of ECM components to the cell surface and influence cytoskeleton remodeling. Recent evidence also suggests that CD147 can upregulate various transcription factors leading to multiple downstream signaling events associated with ECM remodeling and invasion .…”