Dr. Weeks’ Comment: As the attention of oncology finally turns AWAY from killing the inconsequential and wrong target: cancer TUMOR cells and towards remedying to critical problem: cancer STEM cells, we find more excellent research describing why, in the words of Prof. Max Wicha MD – member National Cancer Advisory Board, “chemotherapy and radiation therapy make your cancer worse“. These scientists recommend adding HIF inhibitors, but the most centsible option (safe, effective and cost-effective) is to add anti-inflammatory agents – especially safe, seed-based, oil-mediated anti-inflammatory agents like black cumin seed, black raspberry seed and Chardonnay grape seed .
Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment
- •Exposure of breast cancer cells to carboplatin induces HIF-dependent GSTO1 expression
- •GSTO1 interacts with ryanodine receptor 1 to increase intracellular Ca2+ levels
- •Ca2+ triggers PYK2 â†’ SRC â†’ STAT3 signaling, leading to breast cancer stem cell enrichment
- •GSTO1 knockdown blocks cancer stem cell enrichment, tumor initiation, and metastasis
Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 â†’ SRC â†’ STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer.