Upregulated interleukin‐6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma

Stanam, Aditya; Love-Homan, Laurie; Joseph, Tisha S.; Espinosa-Cotton, Madelyn; Simons, Andrean L.

doi:10.1016/j.molonc.2015.03.008

Cited by 46 publications

(40 citation statements)

References 21 publications

(29 reference statements)

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“…The development and characterization of these ER-HNSCC cells have been previously described [22] and the raw gene expression data has been reported previously [GEO accession #GSE62061]. Combined enrichment analysis of all 4 ER-HNSCC cells compared to their respective ES counterparts revealed that the majority of the top ten deregulated Gene Ontology (GO) processes associated with ER-HNSCC cells are related to stress or stimulus responses (Figure 1A).…”

Section: Resultsmentioning

confidence: 94%

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

et al. 2016

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Erlotinib has demonstrated poor clinical response rates for head and neck squamous cell carcinoma (HNSCC) to date and the majority of respondents acquire resistance to erlotinib relatively quickly. To elucidate novel pathways involved in erlotinib resistance, we compared the gene expression profiles of erlotinib-resistant (ER) vs. erlotinib-sensitive (ES) HNSCC cell lines. Enrichment analysis of microarray data revealed a deregulation of the IL-1 signaling pathway in ER versus ES-HNSCC cells. Gene expression of interleukin-1 alpha (IL1A) and interleukin-1 beta (IL1B) were significantly upregulated by > 2 fold in ER-SQ20B and ER-CAL 27 cells compared to their respective ES-cells. Secretion of the IL-1 receptor antagonist (IL-1RA) was significantly reduced in ER-cells compared to ES-cells. Blockade of IL-1 signaling using a recombinant IL-1R antagonist (anakinra) was able to inhibit the growth of ER-SQ20B and ER-CAL 27 but not ES-SQ20B and ES-CAL 27 xenografts as a single agent and in combination with erlotinib. ER-SQ20B xenografts treated with anakinra ± erlotinib were found to be less vascularized than ER-SQ20B xenografts treated with water or erlotinib. Mice bearing ER-SQ20B xenografts had significantly lesser circulating levels of G-CSF and IL-1β when treated with anakinra ± erlotinib compared to those treated with water or erlotinib alone. Furthermore, augmented mRNA levels of IL1A or interleukin-1 receptor accessory protein (IL1RAP) were associated with shortened survival in HNSCC patients. Altogether, blockade of the IL-1 pathway using anakinra overcame erlotinib resistance in HNSCC xenografts and may represent a novel strategy to overcome EGFR inhibitor resistance for treatment of HNSCC patients.

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Section: Resultsmentioning

confidence: 94%

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

et al. 2016

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“…[26][27][28] An increased autocrine stimulation of the IL-6/STAT3 pathway could unleash the cells from their dependency on EGFR. 27) Notably, increased levels of IL-6 was reported in around 30% of NSCLC patients and in EGFR-TKI treated cell culture.…”

Section: Discussionmentioning

confidence: 99%

“…42) Inhibiting IL-6/STAT3 pathway suppressed cancer cell proliferation and restored the sensitivity to TKI. 26,43) This suggests that the antagonism of IL-6/STAT3 pathway could be therapeutically beneficial for the treatment of drug-resistant tumors that are driven by EMT-like phenomena. 44) In this study, we observed the activation of IL-6/STAT3 signaling pathway in ER cells, elevated IL-6 promotes EMT through altered expression of N-cadherin, vimentin and E-cadherin leading to enhanced cancer invasion.…”

Section: Discussionmentioning

confidence: 99%

“…Since EMT has been previously reported to be associated with erlotinib resistance and IL-6 activation was reported as a key mechanism underlying EGFR-TKI resis- tance, 11,[26][27][28][29] We examined the IL-6 secretion of HCC827-ER cells. Culture supernatant from HCC827-ER cells contained significantly higher levels of IL-6 as compared with parental cells.…”

Section: Acquired Resistance Of the Egfr-tki Inhibitor Erlotinib In Hmentioning

confidence: 99%

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Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

Lou

Yan

Zhu

et al. 2017

Biological & Pharmaceutical Bulletin

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Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial-mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.

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“…This receptor complex then regulates the Janus kinase-signal transducer and activator of transcription 3 (STAT3) pathway, as well as other signaling pathways [21, 22]. Activation of the IL-6/STAT3 pathway has been shown to result into a range of tumor-promoting effects, including (a) stimulation of cancer cell proliferation via direct control of cell cycle-associated proteins [23]; (b) activation of tumor cell survival pathways that could contribute to resistance to anti-cancer therapeutics [24]; (c) induction of tumor EMT which, as indicated below, could facilitate tumor migration and invasiveness and enhance metastatic dissemination; and (d) modulation of infiltrating immune cells by directly affecting the differentiation of myeloid cells [25]. Attesting to the tumor-promoting effect of this inflammatory cytokine, high levels of serum IL-6 have been associated with poor patient clinical outcome [26] and with resistance to therapies [27] in various tumor types.…”

Section: Tumor-driven Inflammation: Key Soluble Immune-mediatorsmentioning

confidence: 99%

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor

Dominguez

David

Palena

2017

Seminars in Cancer Biology

120

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Tumor growth and progression are the products of complex signaling networks between different cell types within the tumor and its surrounding stroma. In particular, established tumors are known to stimulate an inflammatory reaction via the secretion of cytokines, chemokines, and growth factors that favor the recruitment of a range of infiltrating immune cell populations into the tumor microenvironment. While potentially able to exert tumor control, this inflammatory reaction is typically seized upon by the tumor to promote its own growth and progression towards metastasis. This review focuses on recent advances in understanding how an established tumor can initiate an inflammatory response via the release of pro-inflammatory mediators, such as IL-6 and IL-8, and their roles in cancer metastasis. In particular, the role of the epithelial-mesenchymal transition (EMT), a phenotypic switch observed in carcinomas that promotes progression towards metastasis, is discussed here in relation to cancer inflammation.

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Upregulated interleukin‐6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma

Cited by 46 publications

References 21 publications

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor

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