Inhibition of IGF-IR increases chemosensitivity in human colorectal cancer cells through MRP-2 promoter suppression

Ke Shen; Daling Cui; Liyun Sun; Yanhua Lu; Mingquan Han; Jianwen Liu

doi:10.1002/jcb.24080

Inhibition of IGF-IR increases chemosensitivity in human colorectal cancer cells through MRP-2 promoter suppression

J Cell Biochem. 2012 Jun;113(6):2086-97. doi: 10.1002/jcb.24080.

Authors

Ke Shen¹, Daling Cui, Liyun Sun, Yanhua Lu, Mingquan Han, Jianwen Liu

Affiliation

¹ State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237, PR China.

PMID: 22275271
DOI: 10.1002/jcb.24080

Abstract

The emergence of multidrug resistance (MDR) in cancer cells has made many of the currently available chemotherapeutic agents ineffective. However, the mechanism involved in mediating this effect is not yet fully understood. Here, we found the overexpression of type I insulin-like growth factor receptor (IGF-IR) in established colorectal MDR cells. Specific siRNA of IGF-IR decreases cell proliferation, exert synergistic effect with anticancer drugs. The downstream signaling of IGF-IR, PI3K/AKT pathway, was altered upon IGF-IR silencing. The expression of multidrug-resistance-associated protein 2 (MRP-2) was suppressed due to the nuclear translocation of nuclear factor-like 2 (Nrf2). Then the intracellular drug concentration was increased and the drug-resistant phenotype was reversed. Our findings improve current understanding of the biology of IGF-IR and MDR and have significant therapeutic implications on colorectal MDR cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Drug Resistance, Multiple / genetics
Drug Resistance, Neoplasm / genetics
Humans
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins / genetics*
Multidrug Resistance-Associated Proteins / metabolism
NF-E2-Related Factor 2 / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Promoter Regions, Genetic*
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
RNA, Small Interfering
Receptor, IGF Type 1 / antagonists & inhibitors
Receptor, IGF Type 1 / genetics
Receptor, IGF Type 1 / metabolism*
Signal Transduction

Substances

ABCC2 protein, human
Antineoplastic Agents
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
NF-E2-Related Factor 2
RNA, Small Interfering
Receptor, IGF Type 1
Proto-Oncogene Proteins c-akt