Abstract
Chemoresistance in pancreatic cancer has been attributed to tumor-initiating cells (TICs), a minor sub-population of tumor cells. However, the mechanism of chemo-resistance in these cells is still unclear.In the current study, immunohistochemical analysis of LSL-KrasG12D; LSL-Trp53R172H; PdxCre (KPC) murine tumors indicated that hypoxic regions developed through tumor progression. This hypoxic “niche” correlated with increased CD133+ population that had an increased HIF1A activity. Consistent with this observation, CD133+ cells had increased glucose uptake and activity of glycolytic pathway enzymes compared to CD133− cells. Mass spectrometric analysis (UPLC-TQD) following metabolic labeling of CD133+ cells with [13C]-U6 glucose confirmed this observation. Furthermore, although both populations had functionally active mitochondria, CD133+ cells had low mitochondrial complex I and complex IV activity and lesser accumulation of ROS in response to standard chemotherapeutic compounds like paclitaxel, 5FU and gemcitabine. CD133+ cells also showed increased resistance to all three chemotherapeutic compounds and treatment with Glut1 inhibitor (STF31) reversed this resistance, promoting apoptotic death in these cells similar to CD133− cells.Our study indicates that the altered metabolic profile of CD133+ pancreatic TIC protects them against apoptosis, by reducing accumulation of ROS induced by standard chemotherapeutic agents, thereby confering chemoresistance. Since resistance to existing chemotherapy contributes to the poor prognosis in pancreatic cancer, our study paves the way for identifying novel therapeutic targets for managing chemoresistance and tumor recurrence in pancreatic cancer.
Highlights
Pancreatic cancer is a devastating disease with more than 44,000 cases per year in United States alone
To see if this increased glucose uptake influenced the glycolytic activity of CD133+ cells, we studied the expression of glucose metabolizing genes in CD133+ and CD133− cells
To see if LDH and monocarboxylate transporters (MCTs) gene expressions were altered in CD133+ and CD133− cells isolated from multiple KrasG12D; LSL-Trp53R172H; PdxCre (KPC) tumors and patient derived xenografts (PDX) tumors, we studied the expression of these two genes
Summary
Pancreatic cancer is a devastating disease with more than 44,000 cases per year in United States alone. The TICs in pancreatic cancer have been isolated and studied using a number of different surface markers like CD133 [2, 3], CD44, CD24, ESA [4], c-met [5] ALDH [6]. Along with the surface markers, pancreatic cancer TICs have been known to have increased www.impactjournals.com/oncotarget chemo-resistance [7, 8], increased expression of survival genes [3] and anti-apoptotic genes. Recent studies suggest that TICs may have special metabolic properties that distinguish them from the bulk of tumor cells, and that such biochemical properties may constitute a basis for developing new therapeutic strategies to eliminate these cells [9]
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