Additive effects of C(2)-ceramide on paclitaxel-induced premature senescence of human lung cancer cells.

Abstract

AIMS:

the aims of the study are to investigate the additive effect of exogenous short-carbon chain phospholipids, C(2)-ceramide, on an anti-cancer drug paclitaxel (PTX)-induced senescence of human non-small cell lung cancer (NSCLC) cells deficient in functional p53 and p16, and to examine whether mitogen-activated protein kinase (MAPK) plays a role in ceramide-sensitized senescence of NSCLC cells.

MAIN METHODS:

to determine whether exogenous C(2)-ceramide renders lung cancer cells more sensitive to PTX treatment, techniques employing a flow cytometry-based cell cycle analysis and acidic β-galactosidase staining for senescent cells were used. Furthermore, to elucidate the role of MAPK proteins in modulating senescence, assays for protein levels of selective MAPKs and Bcl-2 family members, and detection of transcriptional levels senescence-associated genes were used in the study.

KEY FINDINGS:

a sub-lethal dose of C(2)-ceramide sensitized the NSCLC H1299 cells to PTX treatment. The additive effects of C(2)-ceramide and PTX resulted in proliferative inhibition, G(2)-phase arrest of cell cycle, activation of p38 and eventually premature senescence. Importantly, neither p53, p21(waf1/cip1) nor p16(ink4) was shown to be involved in C(2)-ceramide-sensitized proliferative inhibition and senescence of H1299 cells by PTX in our study.

SIGNIFICANCE:

our study demonstrates that the short-carbon chain C(2)-ceramide can effectively sensitize PTX-induced senescence of H1299 cells via both p21(waf1/cip1)- and p16(ink4)-independent pathways.

• Authors: Jeff Yi-Fu Chen, Chi-Ching Hwang, Wei-Yi Chen, Jing-Ching Lee, Tzu-Fun Fu, Kang Fang, Ying-Chieh Chu, Ya-Lan Huang, Jia-Cheng Lin, Wen-Hui Tsai, Hsueh-Wei Chang, Bing-Hung Chen, Chien-Chih Chiu
• Journal: Life sciences (Life Sci) Vol. 87 Issue 11-12 Pg. 350-7 (Sep 11 2010) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 20624405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Inc. All rights reserved.

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Inhibitor of Apoptosis Proteins
• Microfilament Proteins
• Muscle Proteins
• N-acetylsphingosine
• Osteonectin
• Plasminogen Activator Inhibitor 1
• Proto-Oncogene Proteins c-bcl-2
• SERPINE1 protein, human
• transgelin
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• BIRC3 protein, human
• Baculoviral IAP Repeat-Containing 3 Protein
• Ubiquitin-Protein Ligases
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• beta-Galactosidase
• Caspase 3
• GTP-Binding Proteins
• Sphingosine
• Paclitaxel

Topics

• Apoptosis (drug effects)
• Baculoviral IAP Repeat-Containing 3 Protein
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• Cellular Senescence (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• DNA Fragmentation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• G2 Phase (drug effects)
• GTP-Binding Proteins (genetics)
• Gene Expression (drug effects, genetics)
• Humans
• Inhibitor of Apoptosis Proteins (genetics)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Microfilament Proteins (genetics)
• Muscle Proteins (genetics)
• Osteonectin (genetics)
• Paclitaxel (pharmacology)
• Phosphorylation (drug effects)
• Plasminogen Activator Inhibitor 1 (genetics)
• Protein Glutamine gamma Glutamyltransferase 2
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Sphingosine (analogs & derivatives, pharmacology)
• Transglutaminases (genetics)
• Ubiquitin-Protein Ligases
• beta-Galactosidase (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)