Regulation of MDR1 Expression and Drug Resistance by a Positive Feedback Loop Involving Hyaluronan, Phosphoinositide 3-Kinase, and ErbB2*♦

Abstract

Multidrug resistance is a potent barrier to effective, long term therapy in cancer patients. It is frequently attributed to enhanced expression of multidrug transporters or to the action of receptor kinases, such as ErbB2, and downstream anti-apoptotic signaling pathways, such as the phosphoinositide 3-kinase/Akt pathway. However, very few connections have been made between receptor kinases or anti-apoptotic pathways and multidrug transporter expression or function. Data presented herein show that constitutive interaction of the pericellular polysaccharide, hyaluronan, with its receptor, CD44, regulates assembly and activation of an ErbB2-containing signaling complex, which in turn stimulates phosphoinositide 3-kinase activity in multidrug-resistant MCF-7/Adr human breast carcinoma cells. Phosphoinositide 3-kinase activates Akt and downstream anti-apoptotic events, which contribute to drug resistance. However, hyaluronan and phosphoinositide 3-kinase stimulate expression of the multidrug transporter, MDR1 (P-glycoprotein), in an interdependent, but Akt-independent, manner. Furthermore, constitutively active phosphoinositide 3-kinase, but not Akt, stimulates hyaluronan production. These Akt-independent effects are dominant over the effects of Akt on doxorubicin resistance in MCF-7/Adr cells. Thus hyaluronan, phosphoinositide 3-kinase, and ErbB2 form a positive feedback loop that strongly amplifies MDR1 expression and regulates drug resistance in these cells. This pathway may also be important in progression of other malignant characteristics. These results illustrate the potential importance of hyaluronan as a therapeutic target in multidrug-resistant carcinomas.

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

“…These results are not in agreement with those described by Misra et al 18 and ours. It has been suggested that the reason of these discrepancies could be the difference of the size of the oHA used.…”

“…Previous results in breast carcinoma cell lines have shown that oHA decrease mdr-1 (Pgp) and mrp-2 (Mrp) expression, thus sensitizing these cell lines to doxorubicin. 18 Our findings indicate that components of the extracellular matrix such as oHA may be able to act as Pgp inhibitors both in human and murine resistant cell lines and may be helpful to overcome MDR in Pgp-expressing cells from hematological malignancies.…”

“…17 Recent investigations have shown that oHA reduce constitutive MDR-1 expression in MDR breast tumor cells; in contrast, HA induces MDR-1 expression in drug sensitive cells. 18 Although many studies have been performed in carcinoma models, little is known about the role of oHA and native HA on MDR in hematological malignancies.…”

In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

“…Due to the location of CD44 in the glycolipid-enriched membrane domain (GEM) of the immunological synapse, it can act as a scaffold in T cell activation under conditions of subthreshold activation signals [13,21,24]. Signal transduction is also initiated via interaction of the extracellular domains with neighboring transmembrane receptor tyrosine kinases like the ErbB receptor family [25,26]. Interactions may be direct or indirect via the recruitment of MMP by the heparan sulfate chain of CD44v3 [27,28] and may depend on CD44v expression.…”

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

“…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). Bourguignon et al (2008) have recently shown that HA -CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression and ankyrin-regulated multidrug efflux in breast and ovarian tumour cells.…”