ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer

Abstract

SummaryUterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

“…While few studies have investigated this aspect, there are reports suggesting that, in adipocytes, the observed overexpression of ALDH1A1 is associated with fatty acid synthesis, obesity, insulin resistance (62) as well as lipogenesis and triglyceride production (63). In cancer tissues, the rise in ALDHs is associated with heightened glucose uptake, activation of the glycolytic pathway, and elevation of GLUT1 (64). While the loss of ALDHs coincides with complete loss of glucose utilization in both KO clones, the causal effect, if any, between these two events will need further investigation.…”

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

“…Treatment with NCT-501 inhibited ALDH activity without significant cytotoxicity and reduced the de-differentiation of non-CSC into CSC significantly [81]. In endometrial CSCs, NCT-501 caused significant inhibition of ALDH activity, reduced spheroid cells, and caused selective cell death in ALDH high cells [110].…”

“…Finally, pretreatment with a combination of ATRA and DEAB re-sensitized ALDH high OCSCs to chemotherapeutic drugs paclitaxel and topotecan [82]. In EC patient-derived spheroids, a combination of paclitaxel and ALDH inhibitor DSF chemotherapy demonstrated synergistic inhibition of cancer progression in vivo and in vitro [110]. Reports on combination treatments using ALDH inhibitors in the other gynecologic malignancies were not apparent; however, published studies in OC and EC provide strong rationale for the treatment of chemo-resistant gynecologic malignancies in general with a combination of chemotherapy and ALDH inhibitors to achieve a better outcome in patients.…”

“…In EC cells, Mori el al. demonstrated that CM037 treatment inhibited spheroid formation and preferential death of ALDH high cells [110]. Thus, CM037 is a potential therapeutic to target ALDH1A1 in CSCs in OC and EC; however, further modifications in the structure are required to improve the in vivo stability and bioavailability of the inhibitor.…”

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

“…Additionally, the presence of glucose upregulates the expression of genes associated with the glucose metabolism pathway, such as HK-1, HK-2, c-Myc, Glut-1, PDK-1 etc., which further contributes to the increase in the CSC population in the tumor [ 81 ]. Furthermore, glucose deprivation or glycolysis inhibition results in a proportional decrease in the CSC population [ 82 ]. Contrastingly, in prostate cancer, the stromal cells rely on a “reverse Warburg effect”, where the cancer-associated fibroblasts use aerobic glycolysis as a source of energy and secrete lactate which is taken up by the cancer cells to generate energy using oxidative phosphorylation (OXPHOS) [ 83 ].…”