Abstract
Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy.
Highlights
Pancreatic cancer (PanC) is a devastating disease with an extremely poor prognosis, and ranks as the fifth leading cause of cancer‐related death in Western countries [1]
These studies suggest that altered metabolism and bioenergetic functions together with activated signaling pathways such as PI3K/Akt and ERK1/2 might be the major contributors to gemcitabine resistance in PanC cells, and that the agents which target them could be effective in treating gemcitabine‐resistant (GR) PanC
We investigated the possible bioenergetic and molecular mechanisms underlying the gemcitabine resistance in PanC cells
Summary
Pancreatic cancer (PanC) is a devastating disease with an extremely poor prognosis, and ranks as the fifth leading cause of cancer‐related death in Western countries [1]. The extent of apoptosis was determined by flow cytometry analysis of Annexin V/PI‐stained cells using the fluorescence‐activated cell sorting (FACS) core facility of the University of Colorado Cancer Center (Aurora, CO, USA) In another experiment, GR AsPC‐1 cells were treated with 1‐4% BMJ 24 and 48 h without or with pre‐treatment with autophagy inhibitor 3‐methyladenine (3‐MA) or bafilomycin A1 (BafA1) for 2 h, and cell viability was analyzed by trypan blue assay. (North Billerica, MA, USA) was utilized to detect oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), representing oxidative phosphorylation (OXPHOS) and glycolysis, respectively, in AsPC‐1 cells (both sensitive and resistant). One‐way ANOVA followed by Tukey's test was used for multiple comparisons and statistically significant difference was considered at p≤0.05
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