gemcitabine-resistant phenotype in
pancreatic ductal adenocarcinoma"
Dr. Arnab Ghosh
Kansas City VA Medical Center
Kansas City, MO, USA
12th December, 2018
CDFD Seminar Hall,
Pancreatic ductal adenocarcinoma (PDAC) develops resistance (both extrinsic and intrinsic) by preventing chemotherapeutic agents from entering inside the cells by promoting desmoplastic reactions (DR) and metabolic malfunctions of the drugs. Resistance to gemcitabine (GEM) is associated with these responses. However, the mechanism by which these resistant pathways function in the pancreatic cancer cells remains poorly understood.
Objective: In this study, we have shown that CYR61/CCN1-signaling plays a vital role in making pancreatic cancer cells resistant to GEM in vitro and in-vivo (tumor xenograft model).
Result: We have shown that the catastrophic effect of GEM could significantly be increased in GEM-resistant PDAC cells when CYR61/CCN1 is depleted, while this effect can be suppressed in GEM-sensitive neoplastic cells by treating them with CYR61/CCN1 recombinant protein. On the other hand, non-transformed pancreatic cells, which are sensitive to GEM, cannot be resistant to GEM by CYR61/CCN1 protein treatment, showing a unique feature of CYR61/CCN-signaling that only influences PDAC cells to become resistant. Additionally, we demonstrated that CYR61/CCN1 suppresses the expression of the GEM-activating enzyme dCK while it induces the expression of a DR-promoting factor CTGF (connective tissue growth factor) in pancreatic cancer cells in vitro and in vivo.
Conclusion: dCK and CTGF pathway mediated mechanisms for GEM resistance may act as a novel target for CYR61/CCN1, that protect pancreatic cancer cells from GEM. Collectively, these studies reveal a novel paradigm in which CYR61/CCN1 regulates both extrinsic and intrinsic GEM-resistance in PDAC cells by employing unique signaling pathways.