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.
Misra
Suniti
S
Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Ghatak
Shibnath
S
Zoltan-Jones
Alexandra
A
Toole
Bryan P
BP
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