Abstract | BACKGROUND:
N-butylidenephthalide (BP) exhibits antitumor effect in a variety of cancer cell lines. The objective of this study was to obtain additional insights into the mechanisms involved in BP induced cell death in human prostate cancer cells. METHODS/PRINCIPAL FINDINGS: Two human prostate cancer cell lines, PC-3 and LNCaP, were treated with BP, and subsequently evaluated for their viability and cell cycle profiles. BP caused cell cycle arrest and cell death in both cell lines. The G0/G1 phase arrest was correlated with increase levels of CDK inhibitors (p16, p21 and p27) and decrease of the checkpoint proteins. To determine the mechanisms of BP-induced growth arrest and cell death in prostate cancer cell lines, we performed a microarray study to identify alterations in gene expression induced by BP in the LNCaP cells. Several BP-induced genes, including the GADD153/CHOP, an endoplasmic reticulum stress (ER stress)-regulated gene, were identified. BP-induced ER stress was evidenced by increased expression of the downstream molecules GRP78/BiP, IRE1-α and GADD153/CHOP in both cell lines. Blockage of IRE1-α or GADD153/CHOP expression by siRNA significantly reduced BP-induced cell death in LNCaP cells. Furthermore, blockage of JNK1/2 signaling by JNK siRNA resulted in decreased expression of IRE1-α and GADD153/CHOP genes, implicating that BP-induced ER stress may be elicited via JNK1/2 signaling in prostate cancer cells. BP also suppressed LNCaP xenograft tumor growth in NOD-SCID mice. It caused 68% reduction in tumor volume after 18 days of treatment. CONCLUSIONS:
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Authors | Sheng-Chun Chiu, Shee-Ping Chen, Sung-Ying Huang, Mei-Jen Wang, Shinn-Zong Lin, Horng-Jyh Harn, Cheng-Yoong Pang |
Journal | PloS one
(PLoS One)
Vol. 7
Issue 3
Pg. e33742
( 2012)
ISSN: 1932-6203 [Electronic] United States |
PMID | 22470469
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- DDIT3 protein, human
- Endoplasmic Reticulum Chaperone BiP
- HSPA5 protein, human
- Hspa5 protein, mouse
- Phthalic Anhydrides
- RNA, Small Interfering
- Transcription Factor CHOP
- Cyclin-Dependent Kinase Inhibitor p27
- Mitogen-Activated Protein Kinase 9
- ERN1 protein, human
- Protein Serine-Threonine Kinases
- Mitogen-Activated Protein Kinase 8
- Endoribonucleases
- butylidenephthalide
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Cyclin-Dependent Kinase Inhibitor p16
(metabolism)
- Cyclin-Dependent Kinase Inhibitor p21
(metabolism)
- Cyclin-Dependent Kinase Inhibitor p27
(metabolism)
- Endoplasmic Reticulum Chaperone BiP
- Endoplasmic Reticulum Stress
(drug effects)
- Endoribonucleases
(antagonists & inhibitors, genetics, metabolism)
- G1 Phase Cell Cycle Checkpoints
- Humans
- Male
- Mice
- Mice, Inbred NOD
- Mitogen-Activated Protein Kinase 8
(antagonists & inhibitors, genetics, metabolism)
- Mitogen-Activated Protein Kinase 9
(antagonists & inhibitors, genetics, metabolism)
- Phthalic Anhydrides
(pharmacology)
- Prostatic Neoplasms
- Protein Serine-Threonine Kinases
(antagonists & inhibitors, genetics, metabolism)
- RNA Interference
- RNA, Small Interfering
(metabolism)
- Signal Transduction
- Transcription Factor CHOP
(antagonists & inhibitors, genetics, metabolism)
- Transplantation, Heterologous
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