COMBINED INHIBITION OF AUTOPHAGY AND GLYCOLYSIS SIGNIFICANTLY SABOTAGES PANCREATIC CANCER CELLS

Chuan-shan Yao^{1, 2}, Feng Wang^{1, 3, *}

¹The Medical School, Nankai University, Tianjin 300071, China - ²Department of Oncology, Nanyang First People's Hospital, Henan 473012, China - ³The Laboratory of Acute Abdomen Disease Associated Organ Injury and Repair, Nankai Hospital Affiliated to Nankai University, Tianjin 300100, China

Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers, and KRAS mutation are present in 95% of PDACs. KRAS-mutated PDAC has enhanced dependence on autophagy and glycolysis. However, the mechanism of elevated levels of autophagy and glycolysis in pancreatic cancer cells remains unclear, and intervention of autophagy or glycolysis only inhibits the growth of cancer cells. 

Methods: The levels of autophagy and glycolysis in 5 pancreatic cancer cell lines were determined and MiaPaCa-2 cells were selected. MiaPaCa-2 cells with hypoxia-inducible factor-1α (HIF-1α) low-expression and over-expression were prepared by sh-RNA knockout and transgenic techniques. The effects of HIF-1 on the proliferation, autophagy level, and glycolysis level of pancreatic cancer cells were examined by cell proliferation assay and western blotting. For further study, we investigated the synergistic effects of combined inhibition of autophagy and glycolysis on MiaPaCa-2 and PANC-1 cells. 

Results: There were high basal levels of autophagy and glycolysis in 5 pancreatic cancer cell lines. Spearman correlation analysis indicated that autophagy was moderately correlated with glycolysis in pancreatic cancer cell lines (Normoxia: r = 0.583, p=0.007; Hypoxia: r=0.437, p=0.054). Low-expression of HIF-1α decreased the proliferation, autophagy level, and glycolysis level of MiaPaCa-2 cells under hypoxia, and conversely, over-expression of HIF-1α enhanced the proliferation, autophagy level, and glycolysis level of MiaPaCa-2 cells under hypoxia. Combined inhibition of autophagy and glycolysis significantly decreased glycolysis in MiaPaCa-2 and PANC-1 cells and sabotaged pancreatic cancer cells.

Conclusion: Autophagy is moderately correlated with glycolysis in pancreatic cancer cell lines under normoxia and hypoxia. HIF-1 is a key regulator of autophagy and glycolysis in pancreatic cancer cells under hypoxia. Combined inhibition of autophagy and glycolysis has synergistic effects on pancreatic cancer cells.