Dataset Information

Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance.

ABSTRACT: Preoperative chemotherapy is a promising strategy for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired resistance to chemotherapy is a major obstacle in improving patient prognosis. Cancer-associated fibroblasts (CAFs) are the primary components of the tumor microenvironment and play a crucial role in tumor development; these cells are also potential therapeutic targets for cancer. Using protein arrays, we identified a key secreted cytokine, PAI-1, from CAFs pretreated with cisplatin that was induced after DNA damage of CAFs. The PAI-1 in the tumor microenvironment promoted tumor growth and attenuated the effects of cisplatin treatment. Extracellular PAI-1 activated the AKT and ERK1/2 signaling pathways and inhibited caspase-3 activity and reactive oxygen species accumulation. Tiplaxtinin as a PAI-1 inhibitor could play synergistic effects with cisplatin in vitro and in vivo. In clinical samples, ESCC patients with high expression of PAI-1 in CAFs presented a significantly worse progression-free survival. Taken together, our results showed that PAI-1 secreted from cisplatin-activated CAFs promoted tumor growth and reduced the effects of cisplatin in a paracrine manner, establishing a preclinical rationale to target this cytokine to further improve the clinical response of esophageal squamous cell carcinoma.

SUBMITTER: Che Y

PROVIDER: S-EPMC6037765 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance.

Che Yun Y Wang Jingnan J Li Yuan Y Lu Zhiliang Z Huang Jianbing J Sun Shouguo S Mao Shuangshuang S Lei Yuanyuan Y Zang Ruochuan R Sun Nan N He Jie J

Cell death & disease 20180709 7

Preoperative chemotherapy is a promising strategy for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired resistance to chemotherapy is a major obstacle in improving patient prognosis. Cancer-associated fibroblasts (CAFs) are the primary components of the tumor microenvironment and play a crucial role in tumor development; these cells are also potential therapeutic targets for cancer. Using protein arrays, we identified a key secreted cytokine, PAI-1, from CAFs pretreated with c ...[more]

PMID: 29988148

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Project description:Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance.

Dataset Information

Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance.

Publications

Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance.

Similar Datasets

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