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Published on: October 25, 2018
Regulation of multidrug resistance in cancer cells by hyaluronan
Suniti Misra1, Shibnath Ghatak, Alexandra Zoltan-Jones
1Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Abstract:
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.
Insights
Hyaluronan oligosaccharides suppress cancer cell survival pathways, enhancing chemotherapy effectiveness. This approach also shows intrinsic tumor growth suppression, offering a dual therapeutic strategy.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Drug Resistance Mechanisms
Background:
- Multidrug resistance (MDR) in cancer involves ATP-dependent efflux pumps and altered cell survival/apoptotic signaling.
- Hyaluronan-tumor cell interactions influence cancer cell signaling and growth.
- Previous work showed hyaluronan oligosaccharides suppress phosphoinositide 3-kinase/Akt pathway and reduce tumor growth.
Purpose of the Study:
- To investigate the effect of hyaluronan oligosaccharides on multidrug resistant (MDR) tumor cells.
- To determine if these oligosaccharides can sensitize MDR cells to chemotherapeutic drugs.
- To explore the role of hyaluronan production and emmprin in inducing drug resistance.
Main Methods:
- Treatment of MDR tumor cells with hyaluronan oligosaccharides.
- Analysis of MAP kinase and phosphoinositide 3-kinase signaling pathways.
- Assessment of sensitization to chemotherapeutic agents.
- Investigation of increased hyaluronan production and emmprin expression effects on drug sensitivity.
Main Results:
- Hyaluronan oligosaccharides suppressed both MAP kinase and phosphoinositide 3-kinase pathways in MDR tumor cells.
- These oligomers sensitized MDR cells to various chemotherapeutic drugs.
- Increased hyaluronan production and emmprin expression induced drug resistance in previously sensitive cells.
Conclusions:
- Perturbation of hyaluronan signaling suppresses MDR tumor cell growth and sensitizes them to chemotherapy.
- Hyaluronan signaling modulation offers a potential dual therapeutic strategy in cancer treatment.
- Targeting hyaluronan pathways could overcome chemoresistance and inhibit tumor progression.
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