Figure 4.

Tumor microenvironment affects hENT-1 expression causing chemoresistance. Components of the TME trigger PDAC hENT-1 downregulation and decreased activity. In order: PSCs secrete chemical factors, such as CYR61 and deoxycytidine, which downregulate hENT-1 and compete with drug metabolizing enzymes, respectively; mechanical signaling, such as TGF-β and ROCK, and EMT, triggered by TWIST and ZEB-1, also contribute to hENT-1 decreased activity; hypoxia induces HIF-α/HIF-B heterodimerization, which activates transcription of hypoxia-related genes further decreasing hENT-1 expression. Together these factors cause chemoresistance to drugs which are taken up via hENT-1 (e.g., gemcitabine (GEM) and RX-3117).