Hypoxia‐inducible transgelin 2 selects epithelial‐to‐mesenchymal transition and γ‐radiation‐resistant subtypes by focal adhesion kinase‐associated insulin‐like growth factor 1 receptor activation in non‐small‐cell lung cancer cells

• Published in: Cancer science 2018-11, Vol.109 (11), p.3519-3531
• Main Authors: Kim, In‐Gyu, Lee, Jei‐Ha, Kim, Seo‐Yeon, Hwang, Hai‐Min, Kim, Tae‐Rim, Cho, Eun‐Wie
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; A549 Cells; Actin; AKT protein; Antibiotics; Cancer therapies; Carcinoma, Non-Small-Cell Lung - metabolism; Cell activation; Cell culture; Cell death; Cell Hypoxia; Cell Line, Tumor; Chemotherapy; Cloning; Epithelial-Mesenchymal Transition; Focal adhesion kinase; Focal Adhesions - metabolism; Gamma Rays; Gene Expression Regulation, Neoplastic; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - metabolism; Growth factors; Humans; Hypoxia; IGF1Rβ; Insulin; Kinases; Lithium; Lithium chloride; Lung cancer; Lung Neoplasms - metabolism; Medical prognosis; Mesenchyme; Metastases; Metastasis; Microfilament Proteins - metabolism; Motility; Muscle Proteins - metabolism; Original; Phosphorylation; Proteasomes; Proteins; R&D; Radiation Tolerance; Receptor mechanisms; Receptor, IGF Type 1; Receptors, Somatomedin - metabolism; Research & development; Signal Transduction; Snail1; Stem cells; transgelin 2; Tumors; Up-Regulation; γ‐radiation resistance
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13791

Microenvironment, such as hypoxia common to cancer, plays a critical role in the epithelial‐to‐mesenchymal transition (EMT) program, which is a major route of cancer metastasis and confers γ‐radiation resistance to cells. Herein, we showed that transgelin 2 (TAGLN2), an actin‐binding protein, is significantly induced in hypoxic lung cancer cells and that Snail1 is simultaneously increased, which induces EMT by downregulating E‐cadherin expression. Forced TAGLN2 expression induced severe cell death; however, a small population of cells surviving after forced TAGLN2 overexpression showed γ‐radiation resistance, which might promote tumor relapse and recurrence. These surviving cells showed high metastatic activity with an increase of EMT markers including Snail1. In these cells, TAGLN2 activated the insulin‐like growth factor 1 receptor β (IGF1Rβ)/PI3K/AKT pathway by recruitment of focal adhesion kinase to the IGF1R signaling complex. Activation of the IGF1Rβ/PI3K/AKT pathway also induced inactivation of glycogen synthase kinase 3β (GSK3β), which is involved in Snail1 stabilization. Therefore, both the IGF1Rβ inhibitor (AG1024) and the PI3K inhibitor (LY294002) or AKT inactivation with MK2206 lower the cellular level of Snail1. Involvement of GSK3β was also confirmed by treatment with lithium chloride, the inducer of GSK3β phosphorylation, or MG132, the 26S proteasomal inhibitor, which also stabilized Snail1. In conclusion, the present study provides important evidence that hypoxia‐inducible TAGLN2 is involved in the selection of cancer cells with enhanced EMT properties to overcome the detrimental environment of cancer cells. Hypoxia‐inducible TAGLN2 is involved in enhanced EMT properties to overcome the detrimental environment of cancer cells. Under hypoxic conditions, TAGLN2 was significantly induced, and the cellular level of Snail1, which induces EMT by downregulating E‐cadherin expression, was also increased.