Induction of Epithelial-Mesenchymal Transition via Activation of Epidermal Growth Factor Receptor Contributes to Sunitinib Resistance in Human Renal Cell Carcinoma Cell Lines

Mizumoto, Atsushi; Yamamoto, Kazuhiro; Nakayama, Yuko; Takara, Kohji; Nakagawa, Tsutomu; Hirano, Takeshi; Hirai, Midori

doi:10.1124/jpet.115.226639

Cited by 33 publications

(25 citation statements)

References 41 publications

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“…Hypoxia has traditionally been viewed as a consequence of malignant tumor growth, and it is now widely appreciated to play a critical role in the development and progression of tumors . It has been reported that long‐term treatment with VEGFR2 kinase inhibitors may cause tumor progression, partially because of hypoxia‐induced epithelial to mesenchymal transition (EMT) . However, some reports have shown that VEGFR inhibitors significantly inhibit hypoxia‐induced EMT and tumor progression .…”

Section: Discussionmentioning

confidence: 99%

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor

et al. 2018

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Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor‐2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP‐binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC 50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF‐induced signaling and cell proliferation in HUVEC with picomolar IC 50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well‐known tyrosine kinase inhibitor sunitinib, once‐daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well‐tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.

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Section: Discussionmentioning

confidence: 99%

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor

et al. 2018

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“…Surprisingly, many basic pre-clinical RCC studies employing functional research on “renal cancer/renal carcinoma/renal adenocarcinoma/renal cell cancer” cell lines do not analyze the background of the investigated model and analyze different subtypes of RCC together, including wild-type cell lines and those harboring mutations (i.e. VHL) and cell lines of different histotypes [21–23]. The conclusions of such projects may be difficult to interpret, and the value of potential therapeutic targets is rather questionable, as is the true relevance to a particular RCC.…”

Section: Introductionmentioning

confidence: 99%

Choosing the right cell line for renal cell cancer research

Brodaczewska¹,

Szczylik²,

et al. 2016

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Cell lines are still a tool of choice for many fields of biomedical research, including oncology. Although cancer is a very complex disease, many discoveries have been made using monocultures of established cell lines. Therefore, the proper use of in vitro models is crucial to enhance our understanding of cancer. Therapeutics against renal cell cancer (RCC) are also screened with the use of cell lines. Multiple RCC in vitro cultures are available, allowing in vivo heterogeneity in the laboratory, but at the same time, these can be a source of errors. In this review, we tried to sum up the data on the RCC cell lines used currently. An increasing amount of data on RCC shed new light on the molecular background of the disease; however, it revealed how much still needs to be done. As new types of RCC are being distinguished, novel cell lines and the re-exploration of old ones seems to be indispensable to create effective in vitro tools for drug screening and more.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0565-8) contains supplementary material, which is available to authorized users.

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“…3A and 3B). Mizumoto et al [27] suggested that acquired resistance to sunitinib in RCC cells may be related to the activation of EGFR, and thus, increased EGFR in the SNU-333 cells might have a role in resistance, as well as sphere formation.…”

Section: Discussionmentioning

confidence: 99%

Identification of an appropriate cell line for the renal cell carcinoma model

Chang

Ohn

Moon

et al. 2020

Preprint

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Abstract Background Although renal cell carcinoma (RCC) is known to be susceptible to ferroptosis, we found primary RCC cells showed resistance to ferroptosis and aimed to investigate a feasible candidate for an appropriate cell line for the RCC model. Methods Glutathione peroxidase 4 (GPX4) immunostaining was adopted in the RCC tissue microarrays. Normal human proximal tubule cells (HK-2) and RCC cell lines were used for the MTT assay, Western blotting, sphere-forming assay, and orthotopic injection of athymic Balb/c-nude mice. Results GPX4 immunostaining showed low intensity compared to the normal kidney, which coincided with the ferroptosis-susceptibility of RCC. Primary RCC cell lines (Caki-2, SNU-333, SNU-349, and SNU-1272) showed resistance to 5-fluorouracil and a GPX4 inhibitor compared to the HK-2 cells and to metastatic RCC cells (Caki-1). The Caki-2 cells showed increased GPX4 and xCT, and the SNU-333 cells showed increased ferritin heavy chain (FTH1) compared to the other RCC cells. The Caki-2 cells showed increased aSMA, fibronectin, vimentin, and SNAIL, and the SNU-333 cells showed increased aSMA, E-cadherin, and EpCAM. The Caki-2 cells showed increased Sox-2 and CD105, and the SNU-333 cells showed increased c-Myc and Lgr5. The Caki-1 and SNU-333 cells formed spheres in vitro and orthotopic RCC masses in vivo. The injected SNU-333 tumor only showed high intensities of CD10 and PAX8, consistent with the diagnostic criteria for RCC. Conclusions The primary RCC cell lines used in this study were more resistant to ferroptosis and 5-fluorouracil, and the SNU-333 cells showed tumor-initiating capacities in vitro and in vivo. These results suggest that SNU-333 might be suitable as a orthotopic RCC model for future research.

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Induction of Epithelial-Mesenchymal Transition via Activation of Epidermal Growth Factor Receptor Contributes to Sunitinib Resistance in Human Renal Cell Carcinoma Cell Lines

Cited by 33 publications

References 41 publications

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor

Choosing the right cell line for renal cell cancer research

Identification of an appropriate cell line for the renal cell carcinoma model

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