Cancer cells are highly proliferative, invasive, metastatic and initiate angiogenesis. These activities demand plentiful energy and bountiful stores of anabolic precursors, a situation that puts significant strain on metabolic pathways and necessitates juggling of finite resources. However, the location and erratic structural organisation of tumours means they reside in a nutrient-poor environment. The glycolytic phenotype has evolved in cancer cells to provide a suitable balance between bioenergetic and biosynthetic pathways. Does this adopted strategy also support the overexpression of an ATP-dependent transporter (P-glycoprotein) to maintain resistance against chemotherapy? This article highlights the metabolic adaptations used by cancer cells to maintain both a glycolytic phenotype and sustain the activity of P-glycoprotein. We argue that these cells negotiate an energy precipice to achieve these adaptations. Finally, we advocate the use of compounds that place resistant cells expressing P-glycoprotein under further metabolic strain and how uncoupling protein-2 may provide an ideal target for them.
Keywords: P-glycoprotein; chemotherapy; collateral sensitivity; glycolytic phenotype; mitochondria; multidrug resistance; uncoupling protein.
© The Author(s) 2021.