Anti‐Mitotic Chemotherapy Activates CREB and MAPK Associated Survival Signaling in B Cell Lymphoma

Abstract

Cyclic AMP responsive‐element binding protein (CREB) is a transcription factor linked to proliferation and survival of many cell types, including B lymphocytes and B cell lymphomas. Cancer cells can increase resistance to chemotherapy via activating survival signaling pathways, and we investigated whether CREB activating pathways are associated with chemoresistance signaling in B lymphomas. B lymphoma cell lines were treated with anti‐mitotic drugs including etoposide, which induces DNA damage, and colchicine, which promotes microtubule depolymerization. We observed that etoposide and colchicine promoted CREB phosphorylation via signaling pathways involving protein kinase C (PKC) and mitogen activated protein kinases (MAPK). We next tested whether the CREB activating PKC and MAPK pathways influenced chemosensitivity. PKC and MAPK inhibitors, used either singly or in combination with colchicine or etoposide, enhanced B lymphoma growth arrest and cell death. Our results support the continuing study of combination therapies pairing traditional anti‐neoplastic drugs with selective signal transduction inhibitors to combat chemoresistance and increase chemotherapeutic efficacy.