The CD44 Receptor Interacts with P-Glycoprotein to Promote Cell Migration and Invasion in Cancer

Abstract

Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of morbidity and mortality from cancer. For more than two decades, these two important but not clearly related aspects in the biology of cancer have been extensively studied. Specifically, P-glycoprotein and CD44 have been characterized and are known to be determinants of multidrug resistance (MDR) and metastases. Despite this body of knowledge, few reports have linked the two phenotypes and only recently have there been reasons to suspect a direct connection. In this report, we show that a novel physical and genetic interaction between CD44s and P-glycoprotein is in part responsible for the correlation between MDR and invasive potential in cancer cells. P-glycoprotein-specific substrates that interfere with its function reduced in vitro invasion, migration, and the physical colocalization of CD44s and P-glycoprotein. CD44 expression in sensitive cells promoted the expression of P-glycoprotein and the MDR phenotype. RNA interference of MDR1 inhibited the rate of cell migration. These data indicate that there is a close interaction between CD44 and P-glycoprotein that results in the concurrent expression and modulation of two malignant phenotypes, invasion and MDR.

Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P‐glycoprotein activity and PI3K/Akt pathway

“…Moreover, it has been described that Pgp and CD44 coimmunoprecipitate and colocalize in the cell membrane. 35 On the light of these findings, we suggest that oHA interact with CD44 leading to a conformational change in the CD44 receptor and a decrease in Pgp function. Besides, this would support the fact that we observed modulation in Pgp activity but not changes in its expression.…”

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

“…First, expression of CD44 by the tumour cells can increase the interaction with endothelial cells and transmigration across an endothelial monolayer (Fujisaki et al, 1999;Mine et al, 2003;Draffin et al, 2004;Ratliff, 2005). Second, in a wide variety of systems, increased CD44 expression has been shown to correlate strongly with increased invasive potential of tumour cells Jothy, 1999, 2001;Dingemans et al, 2002;Kobayashi et al, 2002;Bourguignon et al, 2003;Xu and Yu, 2003;Kim et al, 2004;Miletti-Gonzalez et al, 2005) and in particular, increasing evidence points to an important role for CD44 in mediating directional cell migration (Alstergren et al, 2004;Avigdor et al, 2004;Zhu et al, 2004Zhu et al, , 2005Miletti-Gonzalez et al, 2005;Tzircotis et al, 2005).…”

Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression

“…A correlation between the expression of MDR1 and CD44 has been found in breast cancer cell lines, which showed that the two proteins colocalise within the cell membrane, that one protein directly influences the expression of the other and that a disruption of this interaction has profound effects on drug resistance, cell migration and in vitro invasion (Miletti-Gonzalez et al, 2005). Specifically, HA binding to CD44 is capable of stimulating MDR1 expression and drug resistance in breast tumour cells through ErbB2 signalling and PI3 kinase/Akt-related survival pathways (Misra et al, 2005).…”