Lapatinib-resistant cancer cells possessing epithelial cancer stem cell properties develop sensitivity during sphere formation by activation of the ErbB/AKT/cyclin D2 pathway

Ohnishi, Yozo; Yasui, Hirofumi; Kakudo, Kenji; Nozaki, Masami

doi:10.3892/or.2016.5073

Cited by 15 publications

(23 citation statements)

References 36 publications

(35 reference statements)

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“…This suggests that lapatinib does not suppress BCSC self-renewal, but may inhibit proliferation of differentiated tumor cells regardless of HER2 status [67]. A recent study reports that a lapatinib-resistant oral squamous cell carcinoma cell line SAS develops sensitivity to lapatinib during sphere-formation through the activation of HER2/AKT/Cyclin D2 pathway [68]. Induced lapatinib resistance in HER2+ BC cells also shows an up-regulated Snail and Vimentin and down-regulated E-cadherin, therefor increasing intrinsic EMT capability [69].…”

Section: Her2 Blockade May Target Bcscsmentioning

confidence: 99%

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Nami

Wang

2017

Cancers

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HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

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Section: Her2 Blockade May Target Bcscsmentioning

confidence: 99%

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Nami

Wang

2017

Cancers

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“…The HSC-4 and Ca9-22 human OSCC cell line was used as an experimental model in this study. HSC-4 and Ca9-22 cells are negative for cancer stemness (41) and responsive to HGF and c-Met inhibitor SU11274 (23). Thus, the effects of curcumin on HGF-induced EMT and the invasive and migratory potential of HSC-4 and Ca9-22 cells were investigated.…”

Section: Discussionmentioning

confidence: 99%

Curcumin inhibits epithelial‑mesenchymal transition in oral cancer cells via c‑Met blockade

Ohnishi

Sakamoto

et al. 2020

Oncol Lett

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Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. OSCC cells are highly invasive, a characteristic that involves epithelial-mesenchymal transition (EMT); the conversion of immotile epithelial cells into motile mesenchymal cells. EMT is involved in the progression of various types of cancer by promoting tumour cell scattering and conferring to these cells cancer stem cell (CSC)-like characteristics, such as self-renewal. Hepatocyte growth factor (HGF) signalling plays an important role in EMT induction and, therefore, contributes to cell invasion and metastasis in cancer. Due to its potential chemopreventative and anti-tumour activities, curcumin has attracted much interest and has been shown to act as a potent EMT inhibitor in various types of cancer. However, at present, the potential effects of curcumin on HGF-induced EMT in OSCC have not been investigated. Here, we demonstrated that HGF signalling could induce EMT in the HSC4 and Ca9-22 OSCC cell lines via the HGF receptor c-Met and downstream activation of the pro-survival ERK pathway. Notably, curcumin inhibited HGF-induced EMT and cell motility in HSC-4 and Ca9-22 cells via c-Met blockade. Therefore, these findings establish curcumin as a candidate drug for OSCC treatment. Furthermore, curcumin was able to effectively inhibit the HGF-induced increase in the levels of vimentin by downregulating the expression of phosphorylated c-Met, an ERK. In conclusion, the results of the present study demonstrated that curcumin was able to reverse HGF-induced EMT, possibly by inhibiting c-Met expression in oral cancer cells, providing a strong basis for the development of novel approaches for the treatment of oral cancer.

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“…Peer-reviewed version available at Cancers 2019, 11, 1552; doi:10.3390/cancers11101552 cell lines, which had little or no sensitivity to AG1478 inhibition displayed anchorage-independent growth and were able to form spheres. We investigated the EGFR-dependence of DU145, a prostate cancer cell line that could form spheres, and found that it was as resistant to AG1478 and cetuximab as the KB cell line [19]. These data suggest that anchorage-dependent growth may be linked to EGFR dependence.…”

Section: Ag1478 Suppresses Growth Of Some Cancer Cell Lines More Effementioning

confidence: 95%

“…We also showed that there were significant differences in the sensitivities of the cells to the inhibitors. In addition, none of the AG1478-sensitive cell lines were capable of anchorage-independent growth and sphere formation [19]. In contrast, the SAS and KB Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 September 2019 doi:10.20944/preprints201909.0037.v1…”

Section: Ag1478 Suppresses Growth Of Some Cancer Cell Lines More Effementioning

confidence: 99%

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Ligand-Independent EGFR Activation by Anchorage Stimulated Src Promotes Cancer Cell Proliferation and Cetuximab Resistance via ErbB3 Phosphorylation

Nozaki

Yasui

Ohnishi

2019

Preprint

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Activation of the EGFR pathway plays an important role in the progression of cancer and is associated with a poor prognosis in patients. The monoclonal antibody cetuximab, which displays EGFR extracellular domain-specific binding, has proven effective in the treatment of locally advanced disease and relapsed/metastatic disease. However, the effects of cetuximab are weaker than those of EGFR tyrosine kinase inhibitors (TKIs). This study investigates differences in the effects on cell growth of cetuximab and EGFR TKI AG1478 at the molecular level using oral squamous cell carcinoma (OSCC) cell lines. First, we found that there were EGFR-inhibitor sensitive (EIS) and EGFR-inhibitor resistant cell lines. The EIS cell lines expressed not only EGFR but also ErbB3, and both were clearly phosphorylated. The levels of phosphorylated ErbB3 were unaffected by cetuximab but were reduced by AG1478. EGFR ligand treatment increased the levels of phosphorylated EGFR but not phosphorylated ErbB3. Moreover, when EIS cell lines that were only capable of anchorage-dependent growth were grown in suspension, cell growth was suppressed and the levels of phosphorylated FAK, Src, and ErbB3 were significantly reduced. The levels of phosphorylated ErbB3 were unaffected by the FAK inhibitor PF573228, but were reduced by Src inhibition. Finally, combining cetuximab and a Src inhibitor produced an additive effect on the inhibition of EIS cell line growth.

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Lapatinib-resistant cancer cells possessing epithelial cancer stem cell properties develop sensitivity during sphere formation by activation of the ErbB/AKT/cyclin D2 pathway

Cited by 15 publications

References 36 publications

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Curcumin inhibits epithelial‑mesenchymal transition in oral cancer cells via c‑Met blockade

Ligand-Independent EGFR Activation by Anchorage Stimulated Src Promotes Cancer Cell Proliferation and Cetuximab Resistance via ErbB3 Phosphorylation

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