Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1–JNK axis
Shuhei Suzuki, Masashi Okada, Tomomi Sanomachi, Keita Togashi, Shizuka Seino, Atsushi Satō, Masahiro Yamamoto, Chifumi Kitanaka
Abstract
models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.