Anti-proliferative action of IL-6R-targeted antibody tocilizumab for non-small cell lung cancer cells

Kim, Na Hyun; Kim, Seong‐Kwan; Kim, Dong‐Soon; Zhang, Dan; Park, Jin‐A; Yi, Hee; Kim, Jin‐Suk; Shin, Ho‐Chul

doi:10.3892/ol.2015.3019

Cited by 41 publications

(36 citation statements)

References 23 publications

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“…Tocilizumab is a humanized anti-human IL-6R antibody and binds to the IL-6-binding site of human IL-6R which competitively inhibits IL-6/IL-6R signaling (19). Tocilizumab has proven useful for treating IL-6-related cancers (20)(21)(22)(23)(24)(25). The therapeutic potential of tocilizumab against ovarian cancer is still not well investigated.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells

et al. 2016

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Abstract. Ovarian cancer is a leading cause of malignant gynecological tumor-related mortality among women. The treatment of ovarian cancer patients continues to be challenging. MicroRNA-106a (miR-106a) is widely expressed in diverse human tumors. In the present study, we investigated the biological and pathological roles of miR-106a in ovarian cancers. We found that miR-106a expression was significantly increased in primary ovarian cancer tissues and ovarian cancer cells compared with the level in normal tissues. Ectopic expression of an miR-106a inhibitor attenuated ovarian cancer cell proliferation and invasion. miR-106a promoted the growth and invasion of SKOV3 cells by targeting phosphatase and tensin homolog (PTEN). Furthermore, the present study revealed that IL-6 inhibited miR-106a expression by activating STAT3. Tocilizumab, a humanized anti-human IL-6R antibody, that competitively inhibits IL-6/IL-6R signaling, did not inhibit the proliferation and invasion of SKOV3 cells. In conclusion, our studies revealed that miR-106a was significantly increased in the ovarian cancer tissues and cell lines. Downregulation of the expression of miR-106a inhibited cell growth and metastasis of ovarian cancer cells. Together, the present study suggests that miR-106a acts as an oncogene in ovarian cancers.

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Section: Discussionmentioning

confidence: 99%

“…Tocilizumab has proven useful in treating IL-6-related cancers (20)(21)(22)(23)(24)(25). we aimed to ascertain whether tocilizumab increases miR-106a expression, thus it may not be effective in ovarian cancers.…”

Section: Tocilizumab Does Not Inhibit the Proliferation And Invasion mentioning

confidence: 99%

MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells

et al. 2016

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“…TGF(-), TGF(+) and MET/return cells were incubated in 48-well cell culture plates in 400 µl medium. Cells were subsequently treated with cisplatin at a concentration of 100 ng/ml and incubated at 37˚C for 48 h. Subsequently, the cell viability was measured using WST-1 solution (EZ-Cytox kit; Daeillab Service Co., Ltd., Seoul, Korea) and the optical density at 450 nm was measured using an ELISA plate reader with Magellan ™ Tracker software version 3.0.0.12 (Tecan Group Ltd., Männedorf, Switzerland) (19).…”

Section: Cellsmentioning

confidence: 99%

“…Western blotting was performed as previously described (19). The whole-cell lysates were extracted with a mixture of RIPA lysis buffer 3, phosphatase inhibitor cocktail and protease inhibitor cocktail, according to the manufacturer's instructions.…”

Section: Cellsmentioning

confidence: 99%

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Sustainability of CD24 expression, cell proliferation and migration, cisplatin-resistance, and caspase-3 expression during mesenchymal-epithelial transition induced by the removal of TGF-β1 in A549 lung cancer cells

et al. 2017

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Abstract. Epithelial-mesenchymal transition (EMT) is a notable mechanism underlying cancer cell metastasis. Transforming growth factor β1 (TGF-β1) has been used to induce EMT; however, there is a lack of information regarding the role of TGF-β1 in mesenchymal-epithelial transition (MET). In the present study, EMT was induced in A549 lung cancer cells using TGF-β1 (TGF-β1-treated group) and MET was induced sequentially from the TGF-β1-treated group by removing the TGF-β1 (MET/return group). Untreated A549 lung cancer cells were used as a control. Characteristic features, including cancer stem cell markers [cluster of differentiation (CD)24, CD44 and CD133], cell proliferation and migration and diverse intracellular mechanisms, were observed in all groups. Using western blot analysis, the TGF-β1-treated group demonstrated increased vimentin and reduced E-cadherin expression, whereas the MET/return group demonstrated the opposite trend. Among cancer stem cell markers, the population of CD24 low cells was reduced in the TGF-β1-treated group. Furthermore, the G2/M phase cell cycle population, cisplatin-sensitivity, and cell proliferation and migration ability were increased in the TGF-β1-treated group. These features were unaltered in the MET/return group when compared to the TGF-β1-treated group. Immunoblotting revealed an increase in the levels of SMAD3, phosphorylated SMAD3, phosphorylated extracellular signal-regulated kinase and caspase-3, and a decrease in active caspase-3 levels in the TGF-β1-treated group. Increased caspase-3 and reduced active caspase-3 levels were observed in the MET/return group, similar to those in the TGF-β1-treated group; however, levels of other signalling proteins were unchanged compared with the control group. EMT induced by TGF-β1 was not preserved; however, stemness-associated properties (CD24 expression, caspase-3 expression, cell proliferation and cisplatin-resistance) were sustained following removal of TGF-β1. IntroductionEpithelial-mesenchymal transition (EMT) is a biological process observed in embryo neural crest formation (1). In order to migrate easily to distant locations, embryonic epithelial cells undergo EMT to become mesenchymal cells (2). In addition to embryonic cells, cancer cells also undergo EMT (3). This phenomenon was proposed as a cancer metastasis hypothesis, in which epithelial cancer cells downregulate E-cadherin to detach from the primary tumour (4). E-cadherin and vimentin, expressed in epithelial and mesenchymal cells, respectively, have been considered as key markers for EMT (5). Reports suggest that several factors, including Snail and Twist, are able to regulate E-cadherin expression (6,7 Abbreviations: EMT, epithelial-mesenchymal transition; TGF-β1, transforming growth factor β1; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; STAT3, signal transducer and activator of transcription 3; NF-κB, nuclear factor-κB

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Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

Alraouji

Aboussekhra

2020

Molecular Carcinogenesis

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Triple‐negative breast cancer (TNBC) is the most aggressive subtype of the disease with lack of recognized molecular targets for therapy. TNBC cells are known to secrete high levels of the proinflammatory cytokines interleukin‐6 (IL‐6) and IL‐8, which promote angiogenesis and favor the growth and spread of the disease. In the present study, we have shown that the humanized anti‐IL‐6 receptor tocilizumab (Actemra) is also a potent inhibitor of IL‐8 in TNBC cells. Similar effect was also obtained by specific IL‐6 inhibition either by small interfering RNA or by neutralizing antibody. Likewise, neutralizing IL‐8 with specific antibody downregulated IL‐8 and inhibited the IL‐6/signal transducer and activator of transcription 3 and nuclear factor‐κB pathways. Interestingly, simultaneous co‐inhibition of IL‐6 and IL‐8 did not increase the effects of the single inhibitors. Additionally, we present clear evidence that tocilizumab has potent antiangiogenic effect. Indeed, tocilizumab abolished the ability of TNBC cells to induce the differentiation of endothelial cells into network‐like tubular structures in vitro and impaired neovascularization in humanized breast orthotopic tumor xenografts. This was associated with tocilizumab‐dependent downregulation of the main proangiogenic factor vascular endothelial growth factor A and its coactivator hypoxia‐inducible factor 1 both in vitro and in vivo. Therefore, tocilizumab could be of great therapeutic value for TNBC patients through targeting angiogenesis.

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Anti-proliferative action of IL-6R-targeted antibody tocilizumab for non-small cell lung cancer cells

Cited by 41 publications

References 23 publications

MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells

MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells

Sustainability of CD24 expression, cell proliferation and migration, cisplatin-resistance, and caspase-3 expression during mesenchymal-epithelial transition induced by the removal of TGF-β1 in A549 lung cancer cells

Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

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