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TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

Department of Pathology, Medical College of Georgia-Augusta University, Augusta, GA 30912, USA
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Departments of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1184;
Received: 8 July 2019 / Revised: 5 August 2019 / Accepted: 11 August 2019 / Published: 15 August 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
PDF [4254 KB, uploaded 16 August 2019]


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. View Full-Text
Keywords: TIMP-1; IL-6; chemoresistance; NSCLC; tumor microenvironment TIMP-1; IL-6; chemoresistance; NSCLC; tumor microenvironment

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Xiao, W.; Wang, L.; Howard, J.; Kolhe, R.; Rojiani, A.M.; Rojiani, M.V. TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC. Cancers 2019, 11, 1184.

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