Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways

Abstract Background Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus nec...

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Main Authors: Shan Zhu, Yulin Xu, Lijun Wang, Shichong Liao, Yuan Wang, Manman Shi, Yi Tu, Yurong Zhou, Wen Wei
Format: Article
Language:English
Published: BMC 2021-01-01
Series:Cancer Cell International
Subjects:
Ras
Online Access:https://doi.org/10.1186/s12935-020-01735-5
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spelling doaj-5cec94fa3f5140cc8ef8e5bf5a31d40b2021-01-17T12:20:59ZengBMCCancer Cell International1475-28672021-01-0121111110.1186/s12935-020-01735-5Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathwaysShan Zhu0Yulin Xu1Lijun Wang2Shichong Liao3Yuan Wang4Manman Shi5Yi Tu6Yurong Zhou7Wen Wei8Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Radiology, Zhongnan Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityAbstract Background Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus necessary. Methods Retrospective analysis was performed to identify potential stratification biomarkers. The levels of ceramide kinase (CERK) was determined in breast cancer patients. The roles of CERK and its downstream signaling pathways were analysed using cellular and biochemical assays. Results CERK upregulation was identified as a biomarker for chemotherapeutic response in TNBC. A > 2-fold change in CERK (from tumor)/CERK (from normal counterpart) was significantly associated with chemo-resistance (OR = 2.66, 95% CI 1.18–7.34), P = 0.04. CERK overexpression was sufficient to promote TNBC growth and migration, and confer chemo-resistance in TNBC cell lines, although this resistance could be overcome via CERK inhibition. Mechanistic studies suggest that CERK mediates intrinsic resistance and inferior response to chemotherapy in TNBC by regulating multiple oncogenic pathways such as Ras/ERK, PI3K/Akt/mTOR, and RhoA. Conclusions Our work provides an explanation for the heterogeneity of chemo-response across TNBC patients and demonstrates that CERK inhibition offers a therapeutic strategy to overcome treatment resistance.https://doi.org/10.1186/s12935-020-01735-5CERKCP-1TNBCChemoresistanceRasBiomarker
collection DOAJ
language English
format Article
sources DOAJ
author Shan Zhu
Yulin Xu
Lijun Wang
Shichong Liao
Yuan Wang
Manman Shi
Yi Tu
Yurong Zhou
Wen Wei
spellingShingle Shan Zhu
Yulin Xu
Lijun Wang
Shichong Liao
Yuan Wang
Manman Shi
Yi Tu
Yurong Zhou
Wen Wei
Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways
Cancer Cell International
CERK
CP-1
TNBC
Chemoresistance
Ras
Biomarker
author_facet Shan Zhu
Yulin Xu
Lijun Wang
Shichong Liao
Yuan Wang
Manman Shi
Yi Tu
Yurong Zhou
Wen Wei
author_sort Shan Zhu
title Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways
title_short Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways
title_full Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways
title_fullStr Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways
title_full_unstemmed Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways
title_sort ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating ras/erk and pi3k/akt pathways
publisher BMC
series Cancer Cell International
issn 1475-2867
publishDate 2021-01-01
description Abstract Background Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus necessary. Methods Retrospective analysis was performed to identify potential stratification biomarkers. The levels of ceramide kinase (CERK) was determined in breast cancer patients. The roles of CERK and its downstream signaling pathways were analysed using cellular and biochemical assays. Results CERK upregulation was identified as a biomarker for chemotherapeutic response in TNBC. A > 2-fold change in CERK (from tumor)/CERK (from normal counterpart) was significantly associated with chemo-resistance (OR = 2.66, 95% CI 1.18–7.34), P = 0.04. CERK overexpression was sufficient to promote TNBC growth and migration, and confer chemo-resistance in TNBC cell lines, although this resistance could be overcome via CERK inhibition. Mechanistic studies suggest that CERK mediates intrinsic resistance and inferior response to chemotherapy in TNBC by regulating multiple oncogenic pathways such as Ras/ERK, PI3K/Akt/mTOR, and RhoA. Conclusions Our work provides an explanation for the heterogeneity of chemo-response across TNBC patients and demonstrates that CERK inhibition offers a therapeutic strategy to overcome treatment resistance.
topic CERK
CP-1
TNBC
Chemoresistance
Ras
Biomarker
url https://doi.org/10.1186/s12935-020-01735-5
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