Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment

Publication date: 21 February 2017
Source:Cell Reports, Volume 18, Issue 8
Author(s): Haiquan Lu, Ivan Chen, Larissa A. Shimoda, Youngrok Park, Chuanzhao Zhang, Linh Tran, Huimin Zhang, Gregg L. Semenza
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 → SRC → 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.

Graphical abstract

Teaser

Lu et al. report that exposure of breast cancer cells to chemotherapy induces HIF-dependent expression of GSTO1, which interacts with RYR1 to increase intracellular Ca²⁺ levels and trigger PYK2 → SRC → STAT3 signaling leading to breast cancer stem cell enrichment. GSTO1 knockdown blocks cancer stem cell enrichment, tumor initiation, and metastasis.


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