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

Haiquan Lu; Ivan Chen; Larissa A Shimoda; Youngrok Park; Chuanzhao Zhang; Linh Tran; Huimin Zhang; Gregg L Semenza

doi:10.1016/j.celrep.2017.02.001

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

Cell Rep. 2017 Feb 21;18(8):1946-1957. doi: 10.1016/j.celrep.2017.02.001.

Authors

Haiquan Lu¹, Ivan Chen¹, Larissa A Shimoda², Youngrok Park¹, Chuanzhao Zhang³, Linh Tran³, Huimin Zhang³, Gregg L Semenza⁴

Affiliations

¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: gsemenza@jhmi.edu.

PMID: 28228260
DOI: 10.1016/j.celrep.2017.02.001

Abstract

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.

Keywords: breast cancer stem cell; chemotherapy; hypoxia-inducible factors; metastasis; pluripotency factors; tumor initiation; tumor recurrence.

MeSH terms

Antineoplastic Agents / pharmacology*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism*
Calcium / metabolism*
Cell Line, Tumor
Cell Transformation, Neoplastic / metabolism
Cytosol / metabolism
Female
Glutathione Transferase / metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
MCF-7 Cells
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / physiology
Ryanodine Receptor Calcium Release Channel / metabolism
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects

Substances

Antineoplastic Agents
Basic Helix-Loop-Helix Transcription Factors
Hypoxia-Inducible Factor 1, alpha Subunit
Ryanodine Receptor Calcium Release Channel
STAT3 Transcription Factor
endothelial PAS domain-containing protein 1
GSTO1 protein, human
Glutathione Transferase
Calcium