Abstract
Hyaluronan (HA) is a major glycosaminoglycan in the extracellular matrix whose expression is tightly linked to multidrug resistance and tumor progression. In this study we investigated HA-induced interaction between CD44 (a HA receptor) and Nanog (an embryonic stem cell transcription factor) in both human breast tumor cells (MCF-7 cells) and human ovarian tumor cells (SK-OV-3.ipl cells). Using a specific primer pair to amplify Nanog by reverse transcriptase-PCR, we detected the expression of Nanog transcript in both tumor cell lines. In addition, our results reveal that HA binding to these tumor cells promotes Nanog protein association with CD44 followed by Nanog activation and the expression of pluripotent stem cell regulators (e.g. Rex1 and Sox2). Nanog also forms a complex with the "signal transducer and activator of transcription protein 3" (Stat-3) in the nucleus leading to Stat-3-specific transcriptional activation and multidrug transporter, MDR1 (P-glycoprotein) gene expression. Furthermore, we observed that HA-CD44 interaction induces ankyrin (a cytoskeletal protein) binding to MDR1 resulting in the efflux of chemotherapeutic drugs (e.g. doxorubicin and paclitaxel (Taxol)) and chemoresistance in these tumor cells. Overexpression of Nanog by transfecting tumor cells with Nanog cDNA stimulates Stat-3 transcriptional activation, MDR1 overexpression, and multidrug resistance. Down regulation of Nanog signaling or ankyrin function (by transfecting tumor cells with Nanog small interfering RNA or ankyrin repeat domain cDNA) not only blocks HA/CD44-mediated tumor cell behaviors but also enhances chemosensitivity. Taken together, these findings suggest that targeting HA/CD44-mediated Nanog-Stat-3 signaling pathways and ankyrin/cytoskeleton function may represent a novel approach to overcome chemotherapy resistance in some breast and ovarian tumor cells displaying stem cell marker properties during tumor progression.
Highlights
Multidrug resistance frequently contributes to the failure of chemotherapeutic drug treatments in patients diagnosed with solid tumors such as breast and ovarian cancers [1]
We observed that HA-CD44 interaction induces ankyrin binding to MDR1 resulting in the efflux of chemotherapeutic drugs (e.g. doxorubicin and paclitaxel (Taxol)) and chemoresistance in these tumor cells
Down regulation of Nanog signaling or ankyrin function blocks HA/CD44-mediated tumor cell behaviors and enhances chemosensitivity. These findings suggest that targeting HA/CD44mediated Nanog-Stat-3 signaling pathways and ankyrin/cytoskeleton function may represent a novel approach to overcome chemotherapy resistance in some breast and ovarian tumor cells displaying stem cell marker properties during tumor progression
Summary
Multidrug resistance frequently contributes to the failure of chemotherapeutic drug treatments in patients diagnosed with solid tumors such as breast and ovarian cancers [1]. Overexpression of ARD in cells transfected with ARDcDNA interferes with CD44-ankyrin binding and impairs HA-dependent and CD44-specific biological activities [43] These observations support the conclusion that CD44-ankyrin interaction is very important for most HA-mediated CD44 functions and tumor cell-specific behaviors (14, 19 –21, 32, 43, 44). These findings confirm the essential role of Nanog in regulating a variety of cellular functions Both breast carcinomas/tumor cells and ovarian dysgerminomas have been shown to express common embryonic stem cell markers, including CD44 and Nanog [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28, 68, 69]. The question of whether there is a direct interaction between CD44 and Nanog in HA-mediated signaling and in breast and ovarian cancer progression has yet to be answered
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