Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2.
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.
Misra
Suniti
S
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425, USA. misra@musc.edu
Ghatak
Shibnath
S
Toole
Bryan P
BP
D001943:Breast Neoplasms; D058581:Brevican; D011508:Chondroitin Sulfate Proteoglycans / Q000494:pharmacology; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D019450:Genes, MDR / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D058581:Brevican; D011508:Chondroitin Sulfate Proteoglycans; D004317:Doxorubicin; D014453:Glucuronosyltransferase; D018960:Hyaluronan Receptors; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C546938:BCAN protein, human; C494918:AKT1 protein, human