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Blood, 15 January 2002, Vol. 99, No. 2, pp. 641-648
NEOPLASIA
P-glycoprotein-actin association through ERM family proteins: a
role in P-glycoprotein function in human cells of lymphoid
origin
Francesca Luciani,
Agnese Molinari,
Francesco Lozupone,
Annarica Calcabrini,
Luana Lugini,
Annarita Stringaro,
Patrizia Puddu,
Giuseppe Arancia,
Maurizio Cianfriglia, and
Stefano Fais
From the Laboratory of Immunology and Ultrastructures,
Istituto Superiore di Sanità, Rome, Italy.
P-glycoprotein is a 170-kd glycosylated transmembrane protein,
expressed in a variety of human cells and belonging to the adenosine
triphosphate-binding cassette transporter family, whose membrane
expression is functionally associated with the multidrug resistance
phenotype. However, the mechanisms underlying the regulation of
P-glycoprotein functions remain unclear. On the basis of some evidence
suggesting P-glycoprotein-actin cytoskeleton interaction, this study
investigated the association of P-glycoprotein with ezrin, radixin, and
moesin, a class of proteins that cross-link actin filaments with plasma
membrane in a human cell line of lymphoid origin and that have been
shown to link other ion-pump-related proteins. To this purpose, a
multidrug-resistant variant of CCRF-CEM cells (CEM-VBL100) was
used as a model to investigate the following: (1) the cellular
localizations of P-glycoprotein and ezrin, radixin, and moesin and
their molecular associations; and (2) the effects of ezrin, radixin,
and moesin antisense oligonucleotides on multidrug resistance and
P-glycoprotein function. The results showed that: (1) P-glycoprotein
colocalized and coimmunoprecipitated with ezrin, radixin, and moesin;
and (2) treatment with antisense oligonucleotides for ezrin, radixin,
and moesin restored drug susceptibility consistently with inhibition of
both drug efflux and actin-P-glycoprotein association and induction of
cellular redistribution of P-glycoprotein. These data suggest that
P-glycoprotein association with the actin cytoskeleton through ezrin,
radixin, and moesin is key in conferring to human lymphoid cells a
multidrug resistance phenotype. Strategies aimed at inhibiting
P-glycoprotein-actin association may be helpful in increasing the
efficiency of both antitumor and antiviral therapies.
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