ABSTRACT: Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and
