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(3/3)
Date Issued
2005
Date
2005
Author(s)
鄭安理
DOI
932314B002006
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.
Methods: Fourteen carcinoma cell lines representing breast (MCF-7, MCF-7/MXR1,
MCF-7/TPT300), gastric (AGS, N87,SNU1), lung (H460), cervical (SiHa, HeLa, Caski), liver
(Hep3B, Hut7), and nasopharyngeal (NPC-TW01, NPC-TW04) cancer were selected to assess
the effects of dexamethasone (DEX) on the cell growth and cisplatin chemosensitivity of
common human cancers. Immunohistochemical stain of tissues and cells were done by PA1-511A,
an anti-GR monoclonal antibody.
Results: 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. The GCR contents of the 7 cell
lines affected by DEX were significantly higher than those of the other 7 cell lines unaffected by
DEX (5.2±2.5×10 4 vs 1.3±1.4×10 4 , P=0.005).Only two DEX-unresponsive cell lines
(NPC-TW01 and NPC-TW04) had GCR contents at the high range as those of the 7
DEX-responsive cell lines. On further examination, the function of the endogenous GCR of these
two cell lines was found to be impaired. Further, transfection and expression of a vector encoding
GCR to AGS, a GCR low-expressing and GC non-responsive cell line, increased its susceptibility
to DEX manifested as an increased resistance toward cisplatin. 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 I κ B α 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. 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.
Immunohistochemical studies of human cancer tissues showed that 5 of the 45 (11.1%)
breast cancer and 43 of the 85 (50.6%) non-small cell lung cancer had high GR contents at the
ranges of the glucocorticoid-responsive carcinoma cell lines. High GR expression was detected in
51% of the tumor specimens. The difference in tumor GR expression was not associated with cell
type, gender, age, or stage. The outcome was significantly superior for patients whose tumor
showed high GR expression compared to those with either low expression or non-expression. The
median progression-free survival was 8.0 vs. 5.6 months (p=0.039) and overall survival was 18.1
vs. 10.2 months, (p=0.003), respectively. Almost all these patients have received GC as
antiemetics or allergic preventive treatment during chemotherapy courses, therefore, the effect of
GC on the chemosensitivity in vivo was not evaluable.
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
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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