LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

Naito, Sei; Makhov, Petr; Astsaturov, Igor; Golovine, Konstantin; Tulin, Adrian; Kutikov, Alexander; Uzzo, Robert G.; Kolenko, Vladimir

doi:10.1038/bjc.2017.77

Cited by 30 publications

(40 citation statements)

References 17 publications

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“…Cell lines, once plated, were cultured no longer than 3 weeks. The patient-derived PNX0010 clear cell renal cell carcinoma (ccRCC) cell line was described previously (25). hTERT-RPE1 cells were cultured in DMEM/F-12 medium (Life Technologies) supplemented with 10% FBS plus 1Â penicillin/streptomycin, 1Â Glutamax-I (Gibco/Thermo Fisher Scientific), and 0.01 mg/mL hygromycin B (Life Technologies).…”

Section: Cell Culture Cell Lines and Plasmidsmentioning

confidence: 99%

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Kiseleva

Korobeynikov

Nikonova

et al. 2019

Clinical Cancer Research

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Purpose: For many tumors, signaling exchanges between cancer cells and other cells in their microenvironment influence overall tumor signaling. Some of these exchanges depend on expression of the primary cilium on nontransformed cell populations, as extracellular ligands including Sonic Hedgehog (SHH), PDGFRa, and others function through receptors spatially localized to cilia. Cell ciliation is regulated by proteins that are themselves therapeutic targets. We investigated whether kinase inhibitors of clinical interest influence ciliation and signaling by proteins with ciliary receptors in cancer and other cilia-relevant disorders, such as polycystic kidney disease (PKD).Experimental Design: We screened a library of clinical and preclinical kinase inhibitors, identifying drugs that either prevented or induced ciliary disassembly. Specific bioactive protein targets of the drugs were identified by mRNA depletion. Mechanism of action was defined, and activity of select compounds investigated.Results: We identified multiple kinase inhibitors not previously linked to control of ciliation, including sunitinib, erlotinib, and an inhibitor of the innate immune pathway kinase, IRAK4. For all compounds, activity was mediated through regulation of Aurora-A (AURKA) activity. Drugs targeting cilia influenced proximal cellular responses to SHH and PDGFRa. In vivo, sunitinib durably limited ciliation and ciliarelated biological activities in renal cells, renal carcinoma cells, and PKD cysts. Extended analysis of IRAK4 defined a subset of innate immune signaling effectors potently affecting ciliation.Conclusions: These results suggest a paradigm by which targeted drugs may have unexpected off-target effects in heterogeneous cell populations in vivo via control of a physical platform for receipt of extracellular ligands. Conception and design: A.A. Kiseleva, V.A. Korobeynikov, E.A. Golemis Development of methodology: V.A. Korobeynikov, P. Makhov Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.A. Kiseleva, V.A. Korobeynikov, A.S. Nikonova, P. Zhang, M.B. Einarson Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.A.

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Section: Cell Culture Cell Lines and Plasmidsmentioning

confidence: 99%

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Kiseleva

Korobeynikov

Nikonova

et al. 2019

Clinical Cancer Research

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“…In RCC cell line studies, inhibition of mTORC1 suppressed tumor growth, cell survival, angiogenesis, and metastasis (10,11). Furthermore, our previous studies demonstrated that activation of the PI3K/Akt/mTORC1 pathway enhanced resistance to VEGF-targeted agents in RCC cell lines (12,13). Resistance to the VEGF-targeted agent sunitinib is correlated with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) expression, and restoration of PTEN expression restores sensitivity to sunitinib (12).…”

Section: Introductionmentioning

confidence: 95%

“…Resistance to the VEGF-targeted agent sunitinib is correlated with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) expression, and restoration of PTEN expression restores sensitivity to sunitinib (12). Akt activation by low-density lipoprotein (LDL) addition in RCC cell lines counteracts the anti-tumor effects of the VEGF-targeted agents sunitinib and sorafenib (13). In adition, we have previously reported that high levels of 4EBP1/eIF4E activeation predict higher recurrence rate (14).…”

Section: Introductionmentioning

confidence: 99%

Expression of total and phospho 4EBP1 in metastatic and non‑metastatic renal cell carcinoma

et al. 2019

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Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) is phosphorylated and activated by mammalian target of rapamycin complex 1, which serves as a regulator of cell growth, cell survival, metastasis and angiogenesis in many types of cancer. The aim of this study was to evaluate the role of phosphorylated 4EBP1 (p4EBP1) in primary renal cell carcinoma (RCC) as a biomarker in metastatic RCC (mRCC) and non-mRCC cohorts. Primary tumor tissue from 254 non-mRCC and 60 mRCC patients were immunohistochemically stained for t4EBP1 and p4EBP1. The disease-free interval (DFI) categorized by the expressions and clinical parameters were assessed by univariate and multivariate analysis in the non-mRCC cohort. Then, the cause-specific survival (CSS) was assessed in the mRCC cohort by the same methods as used in the non-mRCC cohort. In the non-mRCC cohort, patients with t4EBP1 expression had no RCC recurrence. Patients with p4EBP1 expression had the shorter DFI in univariate analysis (P=0.037). p4EBP1 and pT1b-4 expression levels were independent predictors for de novo metastasis. In the mRCC cohort, intermediate/poor MSKCC risk, non-clear cell RCC, and no p4EBP1 expression were correlated with poor CSS on multivariate analysis. Expression of p4EBP1 could be a predictive biomarker for de novo metastasis in non-mRCC patient cohort. By contrast, mRCC patients showing no p4EBP1 expression had shorter CSS than patients with p4EBP1 expression.

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“…In the present in vivo study, development of hypercholesterolemic phenotype impelled us to investigate the effect of elevated lipid parameters on the efficacy of sorafenib in HCC cells. To mimic hypercholesterolemic condition in vitro, cells were provided with LDL cholesterol exogenously and evaluated for the response to sorafenib [ 43 ]. Based on initial screening experiments and literature, sorafenib (5 μM) and LDLc (100 μg/ml) concentrations were selected for HepG2 and HuH-7 cells (Additional file 7 : Figure S6).…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of RAF/MEK/ERK pathway has been linked to the anti-proliferative action of sorafenib [ 11 ]. Additionally, LDLc has been shown to activate ERK by promoting phosphorylation of its upstream activators like Raf and MEK [ 43 – 46 ]. Thus, to understand whether LDLc decreases toxicity of sorafenib by interfering with signaling pathways, activation of ERK was checked.…”

Section: Resultsmentioning

confidence: 99%

Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9)

et al. 2018

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BackgroundPCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear.MethodsThe present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia. To support in vivo findings, in vitro approaches were used by incubating HCC cells in culture medium with different glucose concentrations or treating the cells with glucose uptake inhibitors. Impact of hypercholesterolemia on chemotherapy was demonstrated by exogenously providing LDLc followed by appropriate in vitro assays.ResultsWe observed that serum and hepatic PCSK9 level is decreased in mice which were provided with glucose containing water. Interestingly, serum and tumor PCSK9 level was upregulated in HepG2-tumor-bearing mice having access to water containing glucose. Additionally, elevated LDLc is detected in sera of these mice. In vitro studies indicated that PCSK9 expression was increased by high glucose availability with potential involvement of reactive oxygen species (ROS) and sterol regulatory element binding protein-1 (SREBP-1). Furthermore, it is also demonstrated that pre-treatment of cells with LDLc diminishes cytotoxicity of sorafenib in HCC cells.ConclusionTaken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0187-2) contains supplementary material, which is available to authorized users.

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LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

Cited by 30 publications

References 17 publications

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

Expression of total and phospho 4EBP1 in metastatic and non‑metastatic renal cell carcinoma

Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9)

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