TY - JOUR
T1 - Differential effects of thapsigargin analogues on apoptosis of prostate cancer cells
T2 - complex regulation by intracellular calcium
AU - Christensen, Søren Brøgger
AU - Dubois, Charlotte
AU - Abeele, Fabien Vanden
AU - Sehgal, Pankaj
AU - Olesen, Claus
AU - Junker, Steffen
AU - Prevarskaya, Natalia
AU - Møller, Jesper Vuust
PY - 2013/11
Y1 - 2013/11
N2 - The inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA) by thapsigargin (Tg) and Tg-type analogues is considered to trigger cell death by activation of apoptotic pathways. Some of these analogues may be useful as antineoplastic agents after appropriate targeting as peptide conjugated prodrugs to cancer cells. With this in mind, this study evaluates the effect on LNCaP androgen-sensitive cancer cells of thapsigargin substituted with 12-aminododecanoyl linkers and Leu (Leu-8ADT), aspartate (Asp-8ADT) or Boc-8ADT. Our results show that both Leu-8ADT and Asp-8ADT result in rapid ER calcium depletion and an influx of calcium across the plasma membrane by activation of store-operated calcium entry. By contrast, ER Ca2+ depletion by Boc-8ADT is a very slow process that does not perceptibly increase cytosolic Ca2+ and activate store-operated calcium entry, because the inhibition of SERCA with this compound is very slow. Nevertheless, we find that Boc-8ADT is a more efficient inducer of apoptosis than both Tg and Leu-8ADT. Compared with Tg and the other analogues, apoptosis induced by Asp-8ADT is very modest, although this compound also activates store-operated calcium entry and at high concentrations (1 μm) causes severe morphological changes, reflecting decreased cell viability. We conclude that many factors need to be considered for optimization of these compounds in antineoplastic drug design. Among these ER stress induced by Ca2+ endoplasmic reticulum mobilization seems particularly important, whereas the early cytosolic increase of Ca2+ concentration preceding the executive phase of apoptosis appears to be of no, or little, consequence for a subsequent apoptotic effect. Inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA) by thapsigargin (Tg) and Tg analogues is considered to trigger cell death by activation of calcium mediated apoptotic pathways. The present study evaluates the effect of thapsigargin analogues on prostate cancer cells and among a number of surprising findings demonstrate that an early cytosolic increase of Ca2+ concentration is not involved in apoptosis induction.
AB - The inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA) by thapsigargin (Tg) and Tg-type analogues is considered to trigger cell death by activation of apoptotic pathways. Some of these analogues may be useful as antineoplastic agents after appropriate targeting as peptide conjugated prodrugs to cancer cells. With this in mind, this study evaluates the effect on LNCaP androgen-sensitive cancer cells of thapsigargin substituted with 12-aminododecanoyl linkers and Leu (Leu-8ADT), aspartate (Asp-8ADT) or Boc-8ADT. Our results show that both Leu-8ADT and Asp-8ADT result in rapid ER calcium depletion and an influx of calcium across the plasma membrane by activation of store-operated calcium entry. By contrast, ER Ca2+ depletion by Boc-8ADT is a very slow process that does not perceptibly increase cytosolic Ca2+ and activate store-operated calcium entry, because the inhibition of SERCA with this compound is very slow. Nevertheless, we find that Boc-8ADT is a more efficient inducer of apoptosis than both Tg and Leu-8ADT. Compared with Tg and the other analogues, apoptosis induced by Asp-8ADT is very modest, although this compound also activates store-operated calcium entry and at high concentrations (1 μm) causes severe morphological changes, reflecting decreased cell viability. We conclude that many factors need to be considered for optimization of these compounds in antineoplastic drug design. Among these ER stress induced by Ca2+ endoplasmic reticulum mobilization seems particularly important, whereas the early cytosolic increase of Ca2+ concentration preceding the executive phase of apoptosis appears to be of no, or little, consequence for a subsequent apoptotic effect. Inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA) by thapsigargin (Tg) and Tg analogues is considered to trigger cell death by activation of calcium mediated apoptotic pathways. The present study evaluates the effect of thapsigargin analogues on prostate cancer cells and among a number of surprising findings demonstrate that an early cytosolic increase of Ca2+ concentration is not involved in apoptosis induction.
U2 - 10.1111/febs.12475
DO - 10.1111/febs.12475
M3 - Journal article
C2 - 23927406
SN - 1742-464X
VL - 280
SP - 5430
EP - 5440
JO - F E B S Journal
JF - F E B S Journal
IS - 21
ER -
