Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells

// Alice Nomura 1, 2 , Patricia Dauer 1, 2 , Vineet Gupta 1, 2 , Olivia McGinn 1 , Nivedita Arora 1 , Kaustav Majumdar 1 , Charles Uhlrich III 1 , Joseph Dalluge 3 , Vikas Dudeja 1, 2 , Ashok Saluja 1, 2 , Sulagna Banerjee 1, 2 1 Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA 2 Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA 3 Department of Chemistry, Mass Spectrometry Laboratory, University of Minnesota, Minneapolis, MN, USA Correspondence to: Sulagna Banerjee, email: Sulagna.Banerjee@med.miami.edu Keywords: CD133, tumor initiating cells, metabolism, hypoxia, ROS Received: April 25, 2016 Accepted: July 10, 2016 Published: July 26, 2016 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-Kras G12D ; LSL-Trp53 R172H; 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 [ 13 C]-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.