Not Only Hypoxia- but Radiation-Induced Epithelial-Mesenchymal Transition Is Modulated by Hypoxia-Inducible Factor 1 in A549 Lung Cancer Cells.

Abstract

Hypoxia leads to post-treatment metastasis and recurrences of cancer via the epithelial-mesenchymal transition (EMT). Radiotherapy itself may also contribute to the acquisition of EMT phenotypes. Despite extensive studies on the EMT driven by either hypoxia or radiation stimuli, the molecular mechanisms characterizing these EMT events remain unclear. Thus, we aimed to evaluate the differences in the molecular pathways between hypoxia-induced EMT (Hypo-EMT) and radiation-induced EMT (R-EMT). Further, we investigated the therapeutic effects of HIF-1α inhibitor (LW6) on Hypo-EMT and R-EMT cells. A549 cells, lung adenocarcinoma cell line, acquired enhanced wound-healing activity under both hypoxia and irradiation. Localization of E-cadherin was altered from the cell membrane to the cytoplasm in both hypoxia and irradiated conditions. Of note, the expression levels of vimentin, one of the major EMT markers, was enhanced in irradiated cells, while it decreased under hypoxia condition. Importantly, LW6 significantly blocked EMT-related malignant phenotypes in both Hypo-EMT cells and R-EMT cells with concomitant re-location of E-cadherin onto the cell membrane. Moreover, LW6 deflected stress responsive signalling, JNK, activated sustainably under hypoxic condition, and the blockage of JNK impaired EMT phenotypes. Together, this work demonstrated the molecular events underlying Hypo-EMT and R-EMT, and highlighted HIF-1α as a therapeutic target not only in Hypo- EMT, but also in R-EMT.

• Authors: M Sato, K Hirose, K Ichise, H Yoshino, T Harada, Y Hatayama, H Kawaguchi, M Tanaka, I Fujioka, Y Takai, M Aoki
• Journal: Folia biologica (Folia Biol (Praha)) Vol. 67 Issue 2 Pg. 62-69 ( 2021) ISSN: 0015-5500 [Print] Czech Republic
• PMID: 34624938 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit

Topics

• A549 Cells
• Antigens, CD
• Cadherins
• Cell Hypoxia
• Epithelial-Mesenchymal Transition (radiation effects)
• Humans
• Hypoxia-Inducible Factor 1 (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lung Neoplasms