Elucidation of susceptible factors to endoplasmic reticulum stress-mediated anticancer activity in human hepatocellular carcinoma

Po Cheng Chiang, Jui Ling Hsu, Ting Chun Yeh, Shiow Lin Pan, Jih Hwa Guh

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The initiation of endoplasmic reticulum (ER) stress has been suggested to play potential roles in hepatocarcinogenesis. However, many obstacles remain as to whether ER stress plays a role in carcinogenesis or tumoricide. This study sought to identify the signals that can serve as anticancer effectors in cells in response to ER stress. Tunicamycin (an N-glycosylation inhibitor) inhibited cell proliferation with IC50 values of 0.19 and 0.62 μg/ml in hepatoma (Hep) 3B and HepG2 cells, respectively. It induced G1 arrest of the cell cycle in both cell lines. The anticancer mechanism of tunicamycin was investigated in Hep3B cells. Tunicamycin induced a rapid decline of cyclin D1 and cyclin A expression and an early increase of glucose-related protein (GRP) 78 and growth arrest and DNA damage-inducible transcription factor (GADD) 153 levels. Cyclin A was the most sensitive regulator to tunicamycin-triggered degradation mechanism. The association of p27Kip1 with cyclin D1/cyclin-dependent kinase (Cdk) 4 was also increased by tunicamycin. The inhibition of GADD153 expression by transfection of GADD153 antisense did not modify tunicamycin-induced G1 arrest and cyclin/Cdk expressions. The knockdown of GRP78 expression by the siRNA transfection technique moderately increased tunicamycin-induced apoptosis but not the antiproliferative effect by sulforhodamine B assay. We suggest that tunicamycin induces G1 arrest through down-regulation of cyclins and Cdks, in which cyclin A is more susceptible to ER stress-triggered degradation mechanism in Hep3B cells. The increased association of p27Kip1 with cyclin D1/Cdk4 may also contribute to tunicamycin-induced cell-cycle arrest. GADD153 and GRP78 play a minor role in tunicamycin-mediated antiproliferative effect, although GRP78 moderately inhibits apoptosis in Hep3B cells. These data provide evidence that cell-cycle regulators are susceptible factors in hepatocellular carcinoma (HCC) responsive to ER stress.

Original languageEnglish
Pages (from-to)167-177
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume377
Issue number2
DOIs
Publication statusPublished - Apr 2008
Externally publishedYes

Fingerprint

Tunicamycin
Endoplasmic Reticulum Stress
Human Activities
Hepatocellular Carcinoma
Cyclin A
Cyclin D1
lissamine rhodamine B
Transfection
Cyclin G1
Cyclin-Dependent Kinase 4
Apoptosis
G1 Phase Cell Cycle Checkpoints
Cyclins
Cyclin-Dependent Kinases
Hep G2 Cells
Cell Cycle Checkpoints
Glycosylation
Small Interfering RNA
Inhibitory Concentration 50
DNA Damage

Keywords

  • Cyclin
  • Endoplasmic reticulum stress
  • Hepatocellular carcinoma
  • p27
  • Tunicamycin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Elucidation of susceptible factors to endoplasmic reticulum stress-mediated anticancer activity in human hepatocellular carcinoma. / Chiang, Po Cheng; Hsu, Jui Ling; Yeh, Ting Chun; Pan, Shiow Lin; Guh, Jih Hwa.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 377, No. 2, 04.2008, p. 167-177.

Research output: Contribution to journalArticle

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