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Plasminogen activator inhibitor-1 enhances radioresistance and aggressiveness of non-small cell lung cancer cells.

ABSTRACT: Acquired resistance of tumor cells during treatment limits the clinical efficacy of radiotherapy. Recent studies to investigate acquired resistance under treatment have focused on intercellular communication because it promotes survival and aggressiveness of tumor cells, causing therapy failure and tumor relapse. Accordingly, a better understanding of the functional communication between subpopulations of cells within a tumor is essential to development of effective cancer treatment strategies. Here, we found that conditioned media (CM) from radioresistant non-small cell lung cancer (NSCLC) cells increased survival of radiosensitive cells. Comparative proteomics analysis revealed plasminogen activator inhibitor-1 (PAI-1) as a key molecule in the secretome that acts as an extracellular signaling trigger to strengthen resistance to radiation. Our results revealed that expression and secretion of PAI-1 in radioresistant cells was increased by radiation-induced transcription factors, including p53, HIF-1?, and Smad3. When CM from radioresistant cells was applied to radiosensitive cells, extracellular PAI-1 activated the AKT and ERK1/2 signaling pathway and inhibited caspase-3 activity. Our study also proposed that PAI-1 activates the signaling pathway in radiosensitive cells via extracellular interaction with its binding partners, not clathrin-mediated endocytosis. Furthermore, secreted PAI-1 increased cell migration capacity and expression of EMT markers in vitro and in vivo. Taken together, our findings demonstrate that PAI-1 secreted from radioresistant NSCLC cells reduced radiosensitivity of nearby cells in a paracrine manner, indicating that functional inhibition of PAI-1 signaling has therapeutic potential because it prevents sensitive cells from acquiring radioresistance.

SUBMITTER: Kang J

PROVIDER: S-EPMC5029677 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Plasminogen activator inhibitor-1 enhances radioresistance and aggressiveness of non-small cell lung cancer cells.

Kang JiHoon J Kim Wanyeon W Kwon TaeWoo T Youn HyeSook H Kim Joong Sun JS Youn BuHyun B

Oncotarget 20160401 17

Acquired resistance of tumor cells during treatment limits the clinical efficacy of radiotherapy. Recent studies to investigate acquired resistance under treatment have focused on intercellular communication because it promotes survival and aggressiveness of tumor cells, causing therapy failure and tumor relapse. Accordingly, a better understanding of the functional communication between subpopulations of cells within a tumor is essential to development of effective cancer treatment strategies. ...[more]

PMID: 27004408

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Project description:Purpose:Radiotherapy is a major treatment method for patients with non-small cell lung cancer (NSCLC). However, the presence of radioresistant cancer stem cells (CSCs) may be associated with disease relapse or a poor outcome after radiotherapy. Voltage-gated calcium channel ?2?1 subunit (encoded by the gene CACNA2D1) isoform 5 is a marker of CSCs in hepatocellular carcinoma. This study aimed to investigate the radiosensitivity of ?2?1-high cells in NSCLC cell lines. Materials and methods:NSCLC cell lines A549, H1975, H1299, and PC9 were used. CACNA2D1-knockdown and CACNA2D1-overexpressing cell lines were established by lentiviral infection. Colony formation assay was performed to determine radiosensitivity. Sphere formation assay in serum-free medium was performed to evaluate self-renewal capacity. Proteins associated with DNA damage repair were analyzed by immunofluorescence or Western blot. The monoclonal antibody of ?2?1 was applied alone or in combination with radiation either in vitro or in vivo to determine the anti-tumor effect of the antibody. Results:?2?1-high cells showed greater sphere-forming efficiency than ?2?1-low cells and were relatively resistant to radiation. CACNA2D1 knockdown in A549 cells enhanced radiosensitivity, whereas CACNA2D1 overexpression in PC9 and H1975 cells reduced radiosensitivity, suggesting that ?2?1 imparted radioresistance to NSCLC cells. Analysis of proteins involved in DNA damage repair suggested that ?2?1 enhanced the efficiency of DNA damage repair. The monoclonal antibody of ?2?1 had a synergistic effect with that of radiation to block the self-renewal of ?2?1-high cells and enhanced the radiosensitivity of ?2?1-positive cells in colony formation assays. The combination of the ?2?1 antibody with radiation repressed A549 xenograft growth in vivo. Conclusion:?2?1 enhances radioresistance in cancer stem-like cells in NSCLC. The ?2?1 monoclonal antibody sensitizes ?2?1-high cells to radiation, suggesting that the antibody may be used to improve the treatment outcome when combined with radiation in NSCLC.

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Plasminogen activator inhibitor-1 enhances radioresistance and aggressiveness of non-small cell lung cancer cells.

Publications

Plasminogen activator inhibitor-1 enhances radioresistance and aggressiveness of non-small cell lung cancer cells.

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