Lectin, Galactoside-Binding Soluble 3 Binding Protein Promotes 17-N-Allylamino-17-demethoxygeldanamycin Resistance through PI3K/Akt Pathway in Lung Cancer Cell Line.
Heat shock protein 90 (HSP90) stabilizing oncoproteins has been an attractive target in cancer therapy. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, was tested in phase II/III clinical trials, but due to lack of efficacy, clinical evaluation of 17-AAG has achieved limited success, which led to resistance to 17-AAG. However, the mechanism of 17-AAG resistance has not clearly been identified. Here, we identified LGALS3BP (Lectin, galactoside-binding soluble 3 binding protein), a secretory glycoprotein, as a 17-AAG resistance factor. In the clinical reports, it was suggested that LGALS3BP was associated with low survival rate, development of cancer progression, and enhancement of metastasis in human cancers. As we confirmed that the LGALS3BP level was increased in 17-AAG-resistant cells (H1299_17R) compared with that of the parental cell line (H1299_17P), knockdown of LGALS3BP expression increased sensitivity to 17-AAG in H1299_17R cells. Overexpression of LGALS3BP also augmented PI3K/Akt and ERK signaling pathways. Furthermore, we determined that the PI3K/Akt signaling pathway was involved in LGALS3BP-mediated 17-AAG resistancein vitroandin vivo, demonstrating that LGALS3BP mediates the resistance against 17-AAG through PI3K/Akt activation rather than ERK activation. These findings suggest that LGALS3BP would be a target to overcome resistance to 17-AAG in lung cancer. For example, the combination of 17-AAG and PI3K/Akt inhibitor would effectively suppress acquired resistance to 17-AAG. In conclusion, targeting of LGALS3BP-mediated-specific survival signaling pathway in resistant cells may provide a novel therapeutic model for the cancer therapy.Mol Cancer Ther; 16(7); 1355-65. ©2017 AACR.
Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|College of Pharmacy, Gachon University, Incheon, Republic of Korea.
Jong Kyu
JK
Woo
College of Pharmacy, Gachon University, Incheon, Republic of Korea.
Jeong-Eun
JE
Jang
Research Institute National Cancer Center, Goyang-si, Republic of Korea.
Ju-Hee
JH
Kang
Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Je Kyung
JK
Seong
Laboratory of Anatomy and Cell Biology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Yeo Sung
YS
Yoon
Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si, Republic of Korea.
Hyoung-Chin
HC
Kim
Research Institute National Cancer Center, Goyang-si, Republic of Korea. eyeball@gachon.ac.kr leesj@ncc.re.kr.
Sang-Jin
SJ
Lee
College of Pharmacy, Gachon University, Incheon, Republic of Korea. eyeball@gachon.ac.kr leesj@ncc.re.kr.
Seung Hyun
SH
Oh
D000951:Antigens, Neoplasm / Q000235:genetics*; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016326:Extracellular Matrix Proteins
D000951:Antigens, Neoplasm; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D006023:Glycoproteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C081856:LGALS3BP protein, human; D016326:Extracellular Matrix Proteins; C112765:tanespimycin