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Differential effects of thapsigargin analogues on apoptosis of prostate cancer cells
Author(s) -
Dubois Charlotte,
Vanden Abeele Fabien,
Sehgal Pankaj,
Olesen Claus,
Junker Steffen,
Christensen Søren B.,
Prevarskaya Natalia,
Møller Jesper V.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12475
Subject(s) - thapsigargin , serca , endoplasmic reticulum , apoptosis , chemistry , calcium , microbiology and biotechnology , cancer cell , cytosol , biochemistry , medicine , biology , cancer , atpase , enzyme , organic chemistry
The inhibition of sarcoplasmic reticulum Ca 2+ ‐ ATP ase ( 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 LNC aP androgen‐sensitive cancer cells of thapsigargin substituted with 12‐aminododecanoyl linkers and Leu (Leu‐8 ADT ), aspartate (Asp‐8 ADT ) or Boc‐8 ADT . Our results show that both Leu‐8 ADT and Asp‐8 ADT 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 Ca 2+ depletion by Boc‐8 ADT is a very slow process that does not perceptibly increase cytosolic Ca 2+ and activate store‐operated calcium entry, because the inhibition of SERCA with this compound is very slow. Nevertheless, we find that Boc‐8 ADT is a more efficient inducer of apoptosis than both Tg and Leu‐8 ADT . Compared with Tg and the other analogues, apoptosis induced by Asp‐8 ADT is very modest, although this compound also activates store‐operated calcium entry and at high concentrations (1 μ m ) 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 Ca 2+ endoplasmic reticulum mobilization seems particularly important, whereas the early cytosolic increase of Ca 2+ concentration preceding the executive phase of apoptosis appears to be of no, or little, consequence for a subsequent apoptotic effect.