ABSTRACT
PURPOSE: Adenosine is a multifaceted regulator of tumor progression. It modulates immune cell activity as well as acting directly on tumor cells. The A2b adenosine receptor (A2b-AR) is thought to be an important mediator of these effects. In this study we sought to analyze the contribution of the A2b-AR to the behavior of colorectal cancer cells. PRINCIPAL RESULTS: The A2b-AR antagonist PSB-603 changed cellular redox state without affecting cellular viability. Quantification of cellular bioenergetics demonstrated that PSB-603 increased basal oxygen consumption rates, indicative of enhanced mitochondrial oxidative phosphorylation. Unexpectedly, pharmacological and genetic approaches to antagonize AR-related signalling of PSB-603 did not abolish the response, suggesting that it was AR-independent. PSB-603 also induced acute increases in reactive oxygen species, and PSB-603 synergized with chemotherapy treatment to increase colorectal cancer cell death, consistent with the known link between cellular metabolism and chemotherapy response. MAJOR CONCLUSIONS: PSB-603 alters cellular metabolism in colorectal cancer cells and increases their sensitivity to chemotherapy. Although requiring more mechanistic insight into its A2b-AR-independent activity, our results show that PSB-603 may have clinical value as an anti-colorectal cancer therapeutic.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Mitochondria/drug effects , Oxidative Phosphorylation/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Receptor, Adenosine A2B/drug effects , Sulfonamides/pharmacology , Xanthines/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Endocytosis/drug effects , Fluorouracil/pharmacology , Humans , Mitochondria/metabolism , Organoplatinum Compounds/pharmacology , Oxaliplatin , Oxidation-Reduction , Oxygen Consumption/drug effects , RNA Interference , Receptor, Adenosine A2B/genetics , Receptor, Adenosine A2B/metabolism , Signal Transduction/drug effects , Time Factors , TransfectionABSTRACT
Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference-mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDH(high) cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDH(high) CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618-28. ©2016 AACR.
