Abstract
Elevated tissue inhibitor of metalloproteinase-1 (TIMP-1) is a negative prognosticator in non-small cell lung carcinoma NSCLC patients. This study sought to identify mechanisms whereby TIMP-1 impacts anticancer therapy. Using NSCLC cells and their TIMP-1 knockdown clones, we examined the chemoresistance against two chemotherapeutic agents, Gemcitabine and Cisplatin, as identified by increased apoptosis in the knockdown clones. A bead-based cytokine screening assay identified interleukin-6 (IL-6) as a key factor in chemoresistance. Exogenous human recombinant rhTIMP-1 or rhIL-6 resulted in reduced apoptosis. IL-6 expression was closely correlated with TIMP-1 kinetics and was upregulated by the addition of exogenous TIMP-1 while TIMP-1 neutralizing antibodies delayed IL-6 elevation. IL-6 production was regulated by TIMP-1, exerting its effect via activation of downstream signal transducer and activator of transcription 3 (STAT3) signaling. Both molecules and their documented transcription factors were upregulated and activated in chemoresistant NSCLC cells, confirming the roles of TIMP-1 and IL-6 in chemoresistance. To examine the role of these genes in patients, survival data from lung adenocarcinoma (LUAD) patients was curated from the cancer genome atlas (TCGA) database. Kaplan-Meier analysis found that individuals expressing low TIMP-1 and IL-6 have a higher survival rate and that the two-gene signature was more significant than the single-gene status. We define for the first time, a regulatory relationship between TIMP-1 and IL-6 in NSCLCs, suggesting that the TIMP-1/IL6 axis may be a valuable prognostic biomarker. Therapeutic interventions directed at this dual target may improve overall prognosis while negatively affecting the development of chemoresistance in NSCLC.
Highlights
Lung cancer is responsible for almost one-quarter of all cancer deaths and remains the leading cause of both cancer incidence and mortality globally [1,2]
The knockdown of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene does not affect the proliferation rate in both non-small cell lung carcinoma (NSCLC) cell lines [10]. These cells were analyzed for apoptosis after treatment with Gemcitabine or Cisplatin, which are routinely used as frontline chemotherapeutic agents for lung carcinomas
The Tissue inhibitors of metalloproteinase (TIMPs)-1 KD clones of both H460 and A549 were more sensitive to apoptosis induced by Gemcitabine compared to the normal tissues (NT) controls as determined by flow cytometric analysis (Figure 1A,B) and
Summary
Lung cancer is responsible for almost one-quarter of all cancer deaths and remains the leading cause of both cancer incidence and mortality globally [1,2]. Systemic chemotherapy is the mainstay of treatment, as the primary modality for patients with advanced disease. Even with radiation and surgery, chemotherapy remains a valuable adjuvant therapeutic consideration [3]. These patients clearly benefit from such chemotherapy, it rarely results in a cure with the majority of patients developing recurrences that are chemoresistant but are often more aggressive [4]. Tissue inhibitors of metalloproteinase (TIMPs) are classically identified as tumor-inhibitory by virtue of their ability to curb matrix metalloproteinase (MMP)-dependent activities [5]. Numerous studies have documented that high blood and tissue levels of TIMP-1 in cancer patients are Cancers 2019, 11, 1184; doi:10.3390/cancers11081184 www.mdpi.com/journal/cancers
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