The Kaposi's sarcoma-associated herpesvirus is the causative agent of
primary effusion lymphoma (PEL), for which cytotoxic
chemotherapy represents the standard of care. The high mortality associated with PEL may be explained in part by resistance of these
tumors to
chemotherapy. The membrane-bound
glycoprotein emmprin (CD147) enhances chemoresistance in
tumors through effects on transporter expression, trafficking and interactions. Interactions between
hyaluronan and
hyaluronan receptors on the cell surface also facilitate
emmprin-mediated chemoresistance. Whether
emmprin or
hyaluronan-receptor interactions regulate chemotherapeutic resistance for virus-associated
malignancies is unknown. Using human PEL
tumor cells, we found that PEL sensitivity to
chemotherapy is directly proportional to expression of
emmprin, the lymphatic vessel endothelial
hyaluronan receptor-1 (LYVE-1) and a
drug transporter known as the
breast cancer resistance
protein/ABCG2 (BCRP), and that
emmprin, LYVE-1 and BCRP interact with each other and colocalize on the PEL cell surface. In addition, we found that
emmprin induces chemoresistance in PEL cells through upregulation of BCRP expression, and RNA interference targeting of
emmprin, LYVE-1 or BCRP enhances PEL cell apoptosis induced by
chemotherapy. Finally, disruption of
hyaluronan-receptor interactions using small
hyaluronan oligosaccharides reduces expression of
emmprin and BCRP while sensitizing PEL cells to
chemotherapy. Collectively, these data support interdependent roles for
emmprin, LYVE-1 and BCRP in chemotherapeutic resistance for PEL.