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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1946-1957
Number of pages	12
Journal	Cell Reports
Volume	18
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2017.02.001
State	Published - Feb 21 2017

Keywords

breast cancer stem cell
chemotherapy
hypoxia-inducible factors
metastasis
pluripotency factors
tumor initiation
tumor recurrence

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2017.02.001

Cite this

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title = "Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment",

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",

author = "Haiquan Lu and Ivan Chen and Shimoda, {Larissa A.} and Youngrok Park and Chuanzhao Zhang and Linh Tran and Huimin Zhang and Semenza, {Gregg L.}",

note = "Funding Information: We thank Professor Philip Board of the Australian National University for providing expression vectors encoding wild-type and C32A mutant GSTO1 and Karen Padgett of Novus Biologicals for providing GSTO1, HIF-2α, KLF4, NANOG, SOX2, RYR1, IL-1β, IL-6, p-PYK2, PYK2, SRC, p-STAT3, and STAT3 antibodies. This work was supported by Impact Award W81XWH-12-1-0464 from the Department of Defense. G.L.S. is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at Johns Hopkins University School of Medicine. Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

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doi = "10.1016/j.celrep.2017.02.001",

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T1 - Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment

AU - Lu, Haiquan

AU - Chen, Ivan

AU - Shimoda, Larissa A.

AU - Park, Youngrok

AU - Zhang, Chuanzhao

AU - Tran, Linh

AU - Zhang, Huimin

AU - Semenza, Gregg L.

N1 - Funding Information: We thank Professor Philip Board of the Australian National University for providing expression vectors encoding wild-type and C32A mutant GSTO1 and Karen Padgett of Novus Biologicals for providing GSTO1, HIF-2α, KLF4, NANOG, SOX2, RYR1, IL-1β, IL-6, p-PYK2, PYK2, SRC, p-STAT3, and STAT3 antibodies. This work was supported by Impact Award W81XWH-12-1-0464 from the Department of Defense. G.L.S. is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at Johns Hopkins University School of Medicine. Publisher Copyright: © 2017 The Authors

PY - 2017/2/21

Y1 - 2017/2/21

N2 - 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.

AB - 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.

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KW - hypoxia-inducible factors

KW - metastasis

KW - pluripotency factors

KW - tumor initiation

KW - tumor recurrence

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