TITLE:
Expression of C-Terminal Modified Serine Palmitoyltransferase-1 Alters Chemosensitivity of Inflammation-Associated Human Cancer Cell Lines
AUTHORS:
Tokunbo Yerokun
KEYWORDS:
Cancer Cell Line, Serine Palmitoyltransferase-1, Glutamate, Celecoxib, Sulfasalazine
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.10,
September
4,
2014
ABSTRACT: Background: The human
serine palmitoyltransferase-1, SPTLC1, subunit is emerging as a stress
responsive protein with putative role in modulating cellular stress response
behavior. When compared to the parental cell line, recombinant Glioma cells
expressing C-terminal modified SPTLC1 are found to show resistance to the
cytotoxic effect of polycyclic hydrocarbons, PHs, including the environmental
contaminant 3-methylcholanthrene. This novel functional association of SPTLC1
expression with proliferative capacity is thought to be due, in part, to its
ability for crosstalk with protein regulators of different biological
processes. Whether the effect of SPTLC1 on sensitivity to PHs extends to
therapeutic drugs and the progression of the malignant phenotype is of research
interest. Methods: In the current study, sub-cellular localization was by
immunostaining for SPTLC1 in untreated and chemical treated cells and detection
with confocal microscopy. The effect expressing C-terminal modified SPTLC1, in
cancer cell lines of the inflammation-associated type, has on chemosensitivity
and gene expression was also assessed. Parent Glioma LN18 and SKN-SH cells and
their SPTLC1 recombinants were each treated with Glutamate, an excitatory
neurotransmitter that can participate in both neuronal and excitotoxic
signaling. In addition to the Glioma and SKN-SH cells, the PC3 prostate cancer
and 647V bladder cancer cell lines were also treated with Celecoxib, a potent
inhibitor of cyclooxygenase 2, COX-2, and an anti-inflammatory drug recently
found to have anti-neoplastic activity against several malignancies. Results:
Confocal microscopy revealed that Celecoxib mediates both rapid and enhanced
redistribution of SPTLC1 and COX-2, to focal adhesion sites. In cell viability
assay, SPTLC1 recombinant cells exhibited differential but dose-dependent
resistance to excitotoxic levels of Glutamate. Drug co-treatment with a
non-lethal dose of the potent kinase inhibitor, Sulfasalazine, increased the
anti-proliferation effect of Celecoxib in a dose-dependent manner for all the
cell lines tested. Conclusions: The effect of SPTLC1 expression on cellular
chemosensitivity seen in the present study further highlights possible role of
a C-terminal modified SPTLC1 variant in the biologic modulation of cellular
behavior in response to therapeutic anticancer drugs.