ICAM-3 endows anticancer drug resistance against microtubule-damaging agents via activation of the ICAM-3-AKT/ERK-CREB-2 pathway and blockage of apoptosis.

Abstract

In a previous study, we showed that induction of ICAM-3 endows radioresistance in cervical cancer [1]. To ascertain whether ICAM-3 also promotes anticancer drug resistance, mock control (H1299/pcDNA3) or ICAM-3-expressing stable transfectants (H1299/ICAM-3) of the non-small cell lung cancer (NSCLC) cell line, NCI-H1299, were generated and treated with the microtubule-damaging agents, paclitaxel (TXL) and vincristine (VCS). TXL-/VCS-treated H1299/ICAM-3 cells showed significantly lower levels of apoptosis, activation of caspases-3, 8 or 9, and decrease in anti-apoptotic protein levels, compared to H1299/pcDNA3 cells. Our data clearly indicate that ICAM-3 promotes drug resistance via inhibition of apoptosis. We additionally showed that Akt, ERK, and CREB-2 are located downstream of ICAM-3, and activation of the ICAM-3-Akt/ERK-CREB-2 pathway induces resistance against TXL and VCS. ICAM-3-expressing stable NCI-H460/ICAM-3 transfectant cells and radioresistant SiHa cells endogenously overexpressing ICAM-3 additionally showed drug resistance against TXL and VCS via activation of the ICAM-3-Akt/ERK-CREB-2 pathway. The finding that ICAM-3 endows drug resistance as well as radioresistance supports its potential utility as a major therapeutic target against cancer.

• Authors: Kwang-Chul Ahn, Jae Yeon Choi, Jae-Sung Kim, Sang-Gu Hwang, Wun-Jae Kim, Jong Kuk Park, Hong-Duck Um
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 441 Issue 2 Pg. 507-13 (Nov 15 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 24177012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• ATF2 protein, human
• Activating Transcription Factor 2
• Antigens, CD
• Antineoplastic Agents
• Cell Adhesion Molecules
• ICAM3 protein, human
• Tubulin Modulators
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Activating Transcription Factor 2 (metabolism)
• Antigens, CD (genetics, physiology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Adhesion Molecules (genetics, physiology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Metabolic Networks and Pathways
• Proto-Oncogene Proteins c-akt (metabolism)
• Tubulin Modulators (pharmacology)