title: 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.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Gu, Seoul 139-706, Republic of Korea.
authors.forename: Kwang-Chul
authors.initials: KC
authors.lastname: Ahn
authors.forename: Jae Yeon
authors.initials: JY
authors.lastname: Choi
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C483616:ICAM3 protein, human; D050257:Tubulin Modulators; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Akt; Apoptosis; CREB-2; Drug resistance; ERK; ICAM-3; Paclitaxel; Vincristine