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Regulating Multidrug Resistance with Hyaluronan

Hyaluronan is involved in a positive feedback loop that regulates multidrug resistance.

Multidrug resistance in cancer can be a barrier to effective long term therapy. Resistance is caused by a number of factors such as enhanced expression of multidrug transporters or the action of receptor kinases, such as ErbB2, and downstream anti-apoptotic signaling pathways, such as the phosphoinositide 3-kinase/Akt pathway. However, there has been little evidence linking receptor kinases or anti-apoptotic pathways and multidrug transporter expression or function.

Now, Suniti Misra and colleagues provide this missing evidence and show that the pericellular polysaccharide, hyaluronan, plays an important role in multidrug resistance. Using multidrug-resistant human breast carcinoma cells, the researchers demonstrate that hyaluronan acts upstream and downstream of phosphoinositide 3-kinase and that both hyaluronan and phosphoinositide 3-kinase stimulate expression of the multidrug transporter, MDR1, and induce drug resistance in an interdependent, but Akt independent, manner. Misra et al. also discovered that hyaluronan regulates activation of ErbB2, which in turn stimulates phosphoinositide 3-kinase, which activates Akt. Furthermore, phosphoinositide 3-kinase, but not Akt, stimulates hyaluronan production. Thus, hyaluronan, phosphoinositide 3-kinase, and ErbB2 form a positive feedback loop that strongly amplifies MDR1 expression and regulates drug resistance.

FOOTNOTES

See referenced article, J. Biol. Chem. 2005, 280, 20310-20315

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