PKC zeta mTOR pathway: a new target for rituximab therapy in follicular lymphoma.
Previous studies have documented that, in malignant B cells, rituximab elicits a complex and not yet totally understood signaling network contributing to its antitumor effect. In this context, we investigated the role of protein kinase C zeta (PKCzeta), an atypical PKC isoform, in the cellular response to rituximab. We found that follicular lymphoma cells displayed an increase in PKCzeta expression and activity levels, compared with nonmalignant B cells, and that this enzyme was a critical regulator of the classical MAPK module by stimulating Raf-1 kinase activity. PKCzeta appeared to be a significant contributor of abnormal mTOR regulation in follicular lymphoma cells through a MAPK-dependent mechanism. Rituximab was found to inhibit the PKCzeta/MAPK/mTOR module in these cells but not in other B-cell lymphomas. Importantly, the expression of a constitutively active form of PKCzeta resulted in an efficient protection of these cells toward rituximab. Altogether, our study describes a new regulatory component of mTOR pathway in follicular cell lymphoma and demonstrates that PKCzeta is a target for rituximab. Therefore, PKCzeta could represent an important parameter for rituximab efficacy and a promising target for future targeted therapy in follicular lymphoma.
Leseux
Ludivine
L
INSERM, Unite 563, Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse, France.
Laurent
Guy
G
Laurent
Camille
C
Rigo
Maxime
M
Blanc
Amandine
A
Olive
Daniel
D
Bezombes
Christine
C
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D000069283:Rituximab; D058570:TOR Serine-Threonine Kinases; D000099221:Protein Kinase C zeta
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D011493:Protein Kinase C; D011494:Protein Kinases; D000069283:Rituximab; D058570:TOR Serine-Threonine Kinases; D000099221:Protein Kinase C zeta; C546842:MTOR protein, human