Regulation of multidrug resistance in cancer cells by hyaluronan.
Multidrug resistance in cancer cells is often due to ATP-dependent efflux pumps, but is also linked to alterations in cell survival and apoptotic signaling pathways. We have found previously that perturbation of hyaluronan-tumor cell interaction by treatment with hyaluronan oligosaccharides suppresses the phosphoinositide 3-kinase/Akt cell survival signaling pathway in cancer cells and reduces tumor growth in vivo. Here we find that these oligomers suppress both the MAP kinase and phosphoinositide 3-kinase pathways in multidrug resistant tumor cells and sensitize these cells to a variety of chemotherapeutic drugs. On the other hand, increased hyaluronan production induces resistance in drug-sensitive tumor cells. Likewise, increased expression of emmprin, which is a glycoprotein that is present on the surface of most malignant cancer cells and that stimulates hyaluronan production, also induces increased resistance. Thus, perturbation of hyaluronan signaling may provide a dual therapeutic role, since it has intrinsic suppressive effects on tumor growth as well as sensitizing cancer cells to chemotherapeutic agents.
Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Suniti
S
Misra
Shibnath
S
Ghatak
Alexandra
A
Zoltan-Jones
Bryan P
BP
Toole
D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051926:Basigin; D014408:Biomarkers, Tumor / Q000494:pharmacology; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology* / Q000502:physiology*; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009369:Neoplasms / Q000378:metabolism*; D009844:Oligosaccharides / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C497886:BSG protein, human; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D009844:Oligosaccharides; D051926:Basigin; D004317:Doxorubicin; D006820:Hyaluronic Acid