皮質類固醇影響上皮細胞癌生長及化學藥物敏感性機轉之研究並探討與癌細胞反應模式相關之分子分類(2/3)
Other Title
Studies on the mechanisms of glucocorticoids on the growth and drug
sensitivity of carcinomas, and exploring relevant molecular classification(2/3)
sensitivity of carcinomas, and exploring relevant molecular classification(2/3)
Date Issued
2004
Date
2004
Author(s)
鄭安理
DOI
922314B002105
Abstract
Objectives: Glucocorticoids (GCs) are
commonly co-administered with anti-cancer
drugs such as cisplatin to prevent
drug-induced allergic reaction, nausea, and
vomiting. But little is known regarding the
effects of GCs on the growth and
chemosensitivity of common carcinomas
cells. In our previous study, we have
demonstrated that DEX had mutually exclusive effects on either growth or cisplatin
sensitivity in 7 of the 14 cell lines. DEX
inhibited cell growth of 4 (MCF-7,
MCF-7/MXR1, MCF-7/TPT300, and HeLa),
increased cisplatin cytotoxicity of one (SiHa),
and decreased cisplatin cytotoxicity of 2
(H460 and Hep3B) cells lines. Although the
effect of DEX on these carcinoma cells was
unexpectedly diverse, it remained GC
receptor (GCR) dependent. In this study, we
further explore the mechanism and the
determinant factor on the diverse effect of
DEX effect on the cancer cells. Methods:
Twenty one steroid receptor co-regulators
were examined by RT-PCR in these 14
cancer cell lines. Chromosome
immuno-precipitate with anti-GCR antibody
and then PCR for the promoter area of these
co-regulators was performed. Quantitative
RT-PCR for GCR and immunohistochemico
stain for GCR was performed in breast, lung
and cervical cancer patient’s tumor
specimens. Results: The expressions of
the steroid receptor co-regulators of these cells are examined. Correlation with the
difference between expression of the
coregulators and DEX responsiveness were
also examined. Furthermore, the expressions
of some of the co-regulators were influenced
by the GCR. In human cancer samples, we
demonstrated that some of the breast, lung
and uterine cervical cancer do express high
level of GCR. In MCF7 cells, we found DEX
induced p21 up-regulation and caused G1
phase arrest of MCF-7. Addition of excess
amounts of a structure homologue of DEX,
RU486, completely abolished the growth
suppression effect of DEX, suggesting that
DEX act via GCR-related signal transduction
pathways. Furthers, DEX has no effect on the
growth of MCF-7/GCR(-), an MCF-7
subclone contains vary low levels of GCR
(<1x10 3 /cell). Compared with MCF-7,
MCF-7/GCR(-) contains no detectable level
of CBP300, HDAC1, and significantly lower
levels of NCOR1, TIF2, GCN5L2, and
ARA70. Transfection of GCR RNAi to
MCF-7 cells also resulted in no detectable
level of CBP300, HDAC1, and significantly
lowers levels of NCOR1, TIF2, GCN5L2,
and ARA70. Transfection of human GCR to MCF-7/GCR(-) restored the expression of
GCR and all these co-regulators and
sensitivity to DEX in MCF-7/GCR(-) cells.
Chromosome IP with anti-GCR antibody and
PCR study showed positive result with TIF-2,
imply the possibility of direct regulation of
TIF-2 expression by GCR. In SiHa cells, we
demonstrated that the The cytotoxicity-enhancing effect of GC in SiHa
cells correlated well with its effect on abrogating the cisplatin-induced activation of
NF- κ B. Expression of a dominant-negative truncated IκBα gene in SiHa cells completely
abolished the cytotoxicity-enhancing effect of
DEX. Conclusions: GCs may affect growth
or chemosensitivity of carcinoma cells
containing high concentration of functional
GCR. Although the effects are heterogeneous
and currently unpredictable, our data
underscore the importance of clarifying the
impact on tumor control by the
co-administed GCs to carcinoma patients
receiving chemotherapy. It is mandatory to
identify the molecular and cellular markers
that help predict the diverse effect of GCs on
carcinoma cells.
Subjects
Glucocorticoids
Glucocorticoid
receptor
receptor
Carcinoma
Cell growth
Chemosensitivity
Drug resistance
SDGs
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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