APBB1 reinforces cancer stem cell and epithelial-to-mesenchymal transition by regulating the IGF1R signaling pathway in non-small-cell lung cancer cells.
Amyloid β precursor protein binding family B member 1(APBB1) was first identified as a binding partner of amyloid precursor protein during brain development, but its function in the context of cancer remain unclear. Here we show for the first time that APBB1 is partly associated with intensifying cancer stem cell(CSC) and epithelial-to-mesenchymal transition (EMT) and enhancing radiation-resistant properties of lung cancer cells. We found that APBB1 was highly expressed in ALDH1highCSC-like cells sorted from A549 lung cancer cells. In APBB1-deficient H460 cells with forced overexpression of APBB1, the protein directly interacted with IGF1Rβ, enhanced phosphorylation of IGF1Rβ/PI3K/AKT pathway(activation) and subsequently induced the phosphorylation of GSK3β(inactivation). This phosphorylation stabilized Snail1, a negative regulator of E-cadherin expression, and regulated β-catenin-mediated ALDH1 expression, which are representative markers for EMT and CSCs, respectively. In contrast, suppression of APBB1 expression with siRNA yielded the opposite effects in APBB1-rich A549 cells. We concluded that APBB1 partly regulates the expression of ALDH1. We also found that APBB1 regulates activation of nuclear factor-κB, which is involved in reducing various stresses including oxidative stress, which suggests that APBB1 is associated with γ-radiation sensitivity. Our findings imply that APBB1 plays an important role in the maintenance of EMT-associated CSC-like properties and γ-radiation resistance via activation of IGF1Rβ/AKT/GSK3β pathway in lung cancer cells, highlighting APBB1 as a potential target for therapeutic cancer treatment.
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, South Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-Daero, Yuseong-Gu, Daejeon 305-353, South Korea.
Jei Ha
JH
Lee
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, South Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-Daero, Yuseong-Gu, Daejeon 305-353, South Korea.
Jung Yul
JY
Kim
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, South Korea.
Seo Yeon
SY
Kim
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, South Korea.
Soo Im
SI
Choi
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, South Korea.
Kuk Chan
KC
Kim
Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 25 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea.
Eun Wie
EW
Cho
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, South Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-Daero, Yuseong-Gu, Daejeon 305-353, South Korea. Electronic address: igkim@kaeri.re.kr.
In Gyu
IG
Kim
D000072283:A549 Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011836:Radiation Tolerance; D011879:Radiotherapy Dosage; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects
C091042:APBB1 protein, human; C000597236:IGF1R protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1
ALDH1; APBB1; Cancer stem cell; EMT; IGF1R