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O'neill JP, Velalar CN, Lee DI, Zhang B, Nakanishi T, Tang Y,
Selaru F, Ross D, Meltzer SJ, Hussain A.
Thapsigargin resistance in human prostate cancer cells
Cancer. 2006 Jun 12
BACKGROUND: Thapsigargin is a potent inhibitor of
sarcoplasmic/endoplasmic reticulum Ca2+ ATPases (SERCAs).
thapsigargin-based prodrugs are being developed for the
treatment of prostate cancer (PC). To develop optimal
thapsigargin-based therapeutics it is important to understand
the mechanisms of resistance to thapsigargin that may
potentially occur in cancer cells. METHODS: DU145/thapsigargin
and PC3/thapsigargin cells were derived from human PC DU145 and
PC3 cells, respectively, by incremental exposure to
thapsigargin. Growth assays, Western blot analyses, cDNA
microarrays, semiquantitative and real-time polymerase chain
reaction (PCR), Northern blot analyses, and immunohistochemistry
were used to study these cells. RESULTS: DU145/thapsigargin
cells are 1100-fold and PC3/thapsigargin cells are 1350-fold
resistant to thapsigargin. Although expression of both SERCA and
p-glycoprotein can mediate thapsigargin resistance in hamster
cells, neither is modulated in DU145/thapsigargin cells. In
contrast, in PC3/thapsigargin cells, SERCA, and not
p-glycoprotein, is significantly overexpressed but cannot by
itself account for the 1350-fold resistance to thapsigargin in
these cells. Several genes not previously identified to be
altered by thapsigargin selection are modulated in
DU145/thapsigargin and PC3/thapsigargin cells. Furthermore, the
spectrum of genes modulated in DU145/thapsigargin cells are
distinct from that in PC3/thapsigargin cells, even though both
cells are of prostate origin and share the same
thapsigargin-resistant phenotype. CONCLUSIONS: PC cells can
adapt to SERCA inhibition by thapsigargin. However, they
demonstrate cell type-specific plasticity with respect to gene
expression upon thapsigargin selection. Further, previously not
described mechanisms of resistance appear to be recruited in the
thapsigargin-resistant PC cells, which provide a novel model to
study mechanisms of resistance and adaptation in PC on
thapsigargin-mediated dysregulation of Ca2+ homeostasis.
Copyright 2006 American Cancer Society.
PMID: 16770788
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