Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. / Sehgal, Pankaj; Szalai, Paula; Praetorius, Helle A; Nissen, Poul; Christensen, Søren Brøgger; Engedal, Nikolai; Møller, Jesper Vuust.

In: Journal of Biological Chemistry, Vol. 292, No. 48, 02.10.2017, p. 19656-19673.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Sehgal, P, Szalai, P, Praetorius, HA, Nissen, P, Christensen, SB, Engedal, N & Møller, JV 2017, 'Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response', Journal of Biological Chemistry, vol. 292, no. 48, pp. 19656-19673. https://doi.org/10.1074/jbc.M117.796920

APA

Sehgal, P., Szalai, P., Praetorius, H. A., Nissen, P., Christensen, S. B., Engedal, N., & Møller, J. V. (2017). Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. Journal of Biological Chemistry, 292(48), 19656-19673. https://doi.org/10.1074/jbc.M117.796920

Vancouver

Sehgal P, Szalai P, Praetorius HA, Nissen P, Christensen SB, Engedal N et al. Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. Journal of Biological Chemistry. 2017 Oct 2;292(48):19656-19673. https://doi.org/10.1074/jbc.M117.796920

Author

Sehgal, Pankaj ; Szalai, Paula ; Praetorius, Helle A ; Nissen, Poul ; Christensen, Søren Brøgger ; Engedal, Nikolai ; Møller, Jesper Vuust. / Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 48. pp. 19656-19673.

Bibtex

@article{5942555b021b4578a4f3c1a369dd696e,
title = "Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response",
abstract = "Calcium (Ca2+) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA), disrupts Ca2+ homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA-inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μM) concentrations of Tg and Tg analogs with various long-chain substitutions at the O(8) position extensively inhibit SERCA1a-mediated Ca2+ transport. We also found that in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca2+ stores. This Ca2+ depletion was followed by markedly reduced cell proliferation rates and morphological changes that developed over 2–4 days and culminated in cell death. Interestingly, these changes were not accompanied by bulk increases in cytosolic Ca2+ levels. Moreover, knockdown of two key store-operated Ca2+ entry (SOCE) components, Orai1 and STIM1, did not reduce Tg cytotoxicity, indicating that SOCE and Ca2+ entry are not critical for Tg-induced cell death. However, we observed a correlation between the abilities of Tg and Tg analogs to deplete ER Ca2+ stores and their detrimental effects on cell viability. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response (UPR). We conclude that ER Ca2+ drainage and sustained UPR activation are key for initiation of apoptosis at low concentrations of Tg and Tg analogs, whereas high cytosolic Ca2+ levels and SOCE are not required.",
keywords = "Faculty of Health and Medical Sciences, Thapsigargin, SERCA, Apoptosis, Unfolded Protein Response",
author = "Pankaj Sehgal and Paula Szalai and Praetorius, {Helle A} and Poul Nissen and Christensen, {S{\o}ren Br{\o}gger} and Nikolai Engedal and M{\o}ller, {Jesper Vuust}",
year = "2017",
month = "10",
day = "2",
doi = "10.1074/jbc.M117.796920",
language = "English",
volume = "292",
pages = "19656--19673",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "48",

}

RIS

TY - JOUR

T1 - Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response

AU - Sehgal, Pankaj

AU - Szalai, Paula

AU - Praetorius, Helle A

AU - Nissen, Poul

AU - Christensen, Søren Brøgger

AU - Engedal, Nikolai

AU - Møller, Jesper Vuust

PY - 2017/10/2

Y1 - 2017/10/2

N2 - Calcium (Ca2+) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA), disrupts Ca2+ homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA-inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μM) concentrations of Tg and Tg analogs with various long-chain substitutions at the O(8) position extensively inhibit SERCA1a-mediated Ca2+ transport. We also found that in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca2+ stores. This Ca2+ depletion was followed by markedly reduced cell proliferation rates and morphological changes that developed over 2–4 days and culminated in cell death. Interestingly, these changes were not accompanied by bulk increases in cytosolic Ca2+ levels. Moreover, knockdown of two key store-operated Ca2+ entry (SOCE) components, Orai1 and STIM1, did not reduce Tg cytotoxicity, indicating that SOCE and Ca2+ entry are not critical for Tg-induced cell death. However, we observed a correlation between the abilities of Tg and Tg analogs to deplete ER Ca2+ stores and their detrimental effects on cell viability. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response (UPR). We conclude that ER Ca2+ drainage and sustained UPR activation are key for initiation of apoptosis at low concentrations of Tg and Tg analogs, whereas high cytosolic Ca2+ levels and SOCE are not required.

AB - Calcium (Ca2+) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA), disrupts Ca2+ homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA-inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μM) concentrations of Tg and Tg analogs with various long-chain substitutions at the O(8) position extensively inhibit SERCA1a-mediated Ca2+ transport. We also found that in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca2+ stores. This Ca2+ depletion was followed by markedly reduced cell proliferation rates and morphological changes that developed over 2–4 days and culminated in cell death. Interestingly, these changes were not accompanied by bulk increases in cytosolic Ca2+ levels. Moreover, knockdown of two key store-operated Ca2+ entry (SOCE) components, Orai1 and STIM1, did not reduce Tg cytotoxicity, indicating that SOCE and Ca2+ entry are not critical for Tg-induced cell death. However, we observed a correlation between the abilities of Tg and Tg analogs to deplete ER Ca2+ stores and their detrimental effects on cell viability. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response (UPR). We conclude that ER Ca2+ drainage and sustained UPR activation are key for initiation of apoptosis at low concentrations of Tg and Tg analogs, whereas high cytosolic Ca2+ levels and SOCE are not required.

KW - Faculty of Health and Medical Sciences

KW - Thapsigargin

KW - SERCA

KW - Apoptosis

KW - Unfolded Protein Response

U2 - 10.1074/jbc.M117.796920

DO - 10.1074/jbc.M117.796920

M3 - Journal article

C2 - 28972171

VL - 292

SP - 19656

EP - 19673

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 48

ER -

ID: 184031098