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SUNITI MISRA, PhD
Ghatak
S, Misra S, and Toole BP. Hyaluronan regulates ErbB2
signaling, cell survival and multidrug resistance in cancer
cells. In "HA 2003", eds. E.A. Balazs and V.C. Hascall, in
press.
No abstract available.
Toole BP, Zoltan-Jones A, Misra S,
Ghatak S. Hyaluronan: a critical component of epithelial-mesenchymal
and epithelial-carcinoma transitions. Cells Tissues Organs.
2005;179(1-2):66-72
Hyaluronan plays a central role in the
transition of epithelia to mesenchyme in the embryo and in
the acquisition of transformed properties in carcinoma
cells. In some cases, hyaluronan is both essential and
sufficient for induction of epithelial-mesenchymal
transitions (EMTs). Underlying its role are the effects of
hyaluronan on receptor kinase activities, cell survival
pathways, and multidrug transporters. A more complete
understanding of the mechanisms whereby hyaluronan exerts
its influences on cell behavior will enhance our
understanding of normal and pathological EMTs and may lead
to improved therapies for cancer patients.
Misra S, Ghatak S, Toole BP.
Regulation of MDR1 expression and drug resistance by a
positive feedback loop involving hyaluronan,
phosphoinositide 3-kinase, and ErbB2. J Biol Chem. 2005 May
27;280(21):20310-5 (JBC Paper of the Week)
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.
Ghatak S, Misra S, Toole BP.
Hyaluronan constitutively regulates ErbB2 phosphorylation
and signaling complex formation in carcinoma cells. J Biol
Chem. 2005 Mar 11;280(10):8875-83
Hyaluronan is enriched in many types of
human cancers, and manipulations of hyaluronan expression or
interactions have a major influence on tumor progression in
animal models. Increased ErbB2 activity is characteristic of
several cancers and is responsible for many aspects of
malignant cell behavior in these cancers. In this study we
show that constitutively high levels of active, i.e.
autophosphorylated, ErbB2 in HCT116 colon carcinoma cells
and TA3/St mammary carcinoma cells are dependent on
endogenous hyaluronan-CD44 interaction. Dependence on
hyaluronan-CD44 interaction was demonstrated by the
administration of hyaluronan oligomers, experimentally
induced expression of soluble CD44, and small interfering
RNA knockdown of CD44 expression. On the other hand,
increasing hyaluronan production by overexpression of
hyaluronan synthase 2 or emmprin causes elevated ErbB2
phosphorylation in MCF-7 mammary carcinoma cells, which
normally exhibit low levels of ErbB2 activity. Furthermore,
in HCT116 and TA3/St cells, inhibition of endogenous
hyaluronan-CD44 interaction causes disassembly of a
constitutive, lipid raft-associated, signaling complex
containing phosphorylated ErbB2, CD44, ezrin,
phosphoinositide 3-kinase, and the chaperone molecules,
Hsp90 and cdc37. Stimulation of hyaluronan production in
MCF-7 cells induces assembly of this complex. We conclude
that hyaluronan regulates ErbB2 activity and its
interactions with other signaling factors in carcinoma
cells.
Marieb EA, Zoltan-Jones A, Li R, Misra
S, Ghatak S, Cao J, Zucker S, Toole BP. Emmprin promotes
anchorage-independent growth in human mammary carcinoma
cells by stimulating hyaluronan production. Cancer Res. 2004
Feb 15;64(4):1229-32
Emmprin (CD147; basigin) is a plasma
membrane glycoprotein, enriched on the surface of many
cancer cells, which induces matrix metalloproteinase
synthesis via cell-cell interactions. Elevated emmprin
production causes increased growth in vivo of human mammary
carcinoma cells. In this study, we show that elevation of
emmprin expression in less aggressive human carcinoma cells,
which normally express low emmprin levels, induces the
ability to grow under anchorage-independent conditions. We
also found that elevated emmprin expression stimulates
hyaluronan production and that the effect of emmprin on
anchorage-independent growth is dependent on hyaluronan.
Furthermore, emmprin stimulates cell survival pathway
signaling in a hyaluronan-dependent manner. From these and
other studies we conclude that emmprin enhances several
malignant properties of cancer cells, including
anchorage-independent growth, invasiveness, and
chemoresistance.
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