Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) and autophagy play increasingly important roles in DNA damage repair and cell death. Gemcitabine (GEM) remains the first-line chemotherapeutic drug for pancreatic cancer (PC). However, little is known about the relationship between PARP-1 expression and autophagy in response to GEM. Here we demonstrate that GEM induces DNA-damage response and degradation of mono-ADP ribosylated PARP-1 through the autophagy pathway in PC cells, which is rescued by inhibiting autophagy. Hypoxia and serum starvation inhibit autophagic activity due to abrogated GEM-induced mono-ADP-ribosylated PARP-1 degradation. Activation of extracellular regulated protein kinases (ERK) induced by serum starvation shows differences in intracellular localization as well as modulation of autophagy and PARP-1 degradation in GEM-sensitive KLM1 and -resistant KLM1-R cells. Our study has revealed a novel role of autophagy in PARP-1 degradation in response to GEM, and the different impacts of MEK/ERK signaling pathway on autophagy between GEM-sensitive and -resistant PC cells.
Highlights
Gemcitabine (GEM) is currently the standard treatment for advanced and metastatic pancreatic cancer (PC) in both adjuvant and palliative settings, but resistance to GEM has been a big problem as its response rate has been reduced to,20% [1,2,3,4]
We demonstrated that both light chain 3 (LC3)-I and II were down-regulated in KLM1-R compared to KLM1 cells (Fig. 1 B)
Down-regulation of AMP-activated protein kinase A1 (AMPKa1) and unc-51-like kinase 1 (Ulk1) were shown, unlike phosphatidylinositol 3- kinase (PI3K CIII) or Coiled-coil myosin-like BCL2-interacting protein (Beclin-1), in KLM1-R compared to KLM1 cells (Fig. S1 A and B), indicating that the reduction of autophagic activity in GEMresistant KLM1-R cells may be related to the down-regulation of AMPKa1 and/or Ulk1 expression
Summary
Gemcitabine (GEM) is currently the standard treatment for advanced and metastatic pancreatic cancer (PC) in both adjuvant and palliative settings, but resistance to GEM has been a big problem as its response rate has been reduced to ,20% [1,2,3,4]. GEM can inhibit DNA synthesis by targeting ribonucleotide reductase, leading to its inclusion into cellular DNA, causing DNA replication errors [5,6]. Inhibition of checkpoint kinase 1 (Chk1) with chemical inhibitors induced sensitization of PC cells in response to GEM [8,9]. The evidence has shown the relationship between DNA repair and sensitization of cells to GEM, the mechanisms responsible for the repair of GEM-induced DNA damage are not clearly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
