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

Sei Naito; Peter Makhov; Igor Astsaturov; Konstantin Golovine; Alexei Tulin; Alexander Kutikov; Robert G. Uzzo; Vladimir M. Kolenko

doi:10.1038/bjc.2017.77

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

Sei Naito, Peter Makhov, Igor Astsaturov, Konstantin Golovine, Alexei Tulin, Alexander Kutikov, Robert G. Uzzo, Vladimir M. Kolenko

Fox Chase Cancer Center

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Background:Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.Methods:We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.Results:The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.Conclusions:The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

Original language	English
Pages (from-to)	1203-1207
Number of pages	5
Journal	British Journal of Cancer
Volume	116
Issue number	9
DOIs	https://doi.org/10.1038/bjc.2017.77
State	Published - Mar 25 2017

Keywords

Animals
Carcinoma, Renal Cell/drug therapy
Cell Line, Tumor
Cholesterol, LDL/administration & dosage
Cholesterol/metabolism
Drug Interactions/ethnology
Elafin/genetics
Endothelial Cells/drug effects
Female
Humans
Indoles/administration & dosage
Mice
Protein Kinase Inhibitors/administration & dosage
Proto-Oncogene Proteins c-akt/genetics
Pyrroles/administration & dosage
Signal Transduction/drug effects
Sunitinib
Xenograft Model Antitumor Assays

Access to Document

10.1038/bjc.2017.77

Cite this

@article{d374aa989ed74c3fa9f28cad652fb71c,

title = "LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma",

abstract = "Background:Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.Methods:We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.Results:The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.Conclusions:The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.",

keywords = "Animals, Carcinoma, Renal Cell/drug therapy, Cell Line, Tumor, Cholesterol, LDL/administration & dosage, Cholesterol/metabolism, Drug Interactions/ethnology, Elafin/genetics, Endothelial Cells/drug effects, Female, Humans, Indoles/administration & dosage, Mice, Protein Kinase Inhibitors/administration & dosage, Proto-Oncogene Proteins c-akt/genetics, Pyrroles/administration & dosage, Signal Transduction/drug effects, Sunitinib, Xenograft Model Antitumor Assays",

author = "Sei Naito and Peter Makhov and Igor Astsaturov and Konstantin Golovine and Alexei Tulin and Alexander Kutikov and Uzzo, {Robert G.} and Kolenko, {Vladimir M.}",

year = "2017",

month = mar,

day = "25",

doi = "10.1038/bjc.2017.77",

language = "English",

volume = "116",

pages = "1203--1207",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "9",

}

TY - JOUR

T1 - LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

AU - Naito, Sei

AU - Makhov, Peter

AU - Astsaturov, Igor

AU - Golovine, Konstantin

AU - Tulin, Alexei

AU - Kutikov, Alexander

AU - Uzzo, Robert G.

AU - Kolenko, Vladimir M.

PY - 2017/3/25

Y1 - 2017/3/25

N2 - Background:Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.Methods:We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.Results:The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.Conclusions:The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

AB - Background:Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.Methods:We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.Results:The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.Conclusions:The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

KW - Animals

KW - Carcinoma, Renal Cell/drug therapy

KW - Cell Line, Tumor

KW - Cholesterol, LDL/administration & dosage

KW - Cholesterol/metabolism

KW - Drug Interactions/ethnology

KW - Elafin/genetics

KW - Endothelial Cells/drug effects

KW - Female

KW - Humans

KW - Indoles/administration & dosage

KW - Mice

KW - Protein Kinase Inhibitors/administration & dosage

KW - Proto-Oncogene Proteins c-akt/genetics

KW - Pyrroles/administration & dosage

KW - Signal Transduction/drug effects

KW - Sunitinib

KW - Xenograft Model Antitumor Assays

UR - http://www.scopus.com/inward/record.url?scp=85016421172&partnerID=8YFLogxK

U2 - 10.1038/bjc.2017.77

DO - 10.1038/bjc.2017.77

M3 - Article

C2 - 28350788

SN - 0007-0920

VL - 116

SP - 1203

EP - 1207

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 9

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this