LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation

Chongbiao Huang, Yang Li, Zengxun Li, Yang Xu, Na Li, Yi Ge, Jie Dong, Antao Chang, Tiansuo Zhao, Xiuchao Wang, Hongwei Wang, Shengyu Yang, Keping Xie, Jihui Hao, He Ren

Research output: Contribution to journalArticle

Abstract

Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. Experimental Design: The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics. Results: LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expression was pivotal for tumor cells to survive in the oxygen- glucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth. Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygen- glucose deprivation conditions and is a promising therapeutic target for cancer treatment.

Original languageEnglish (US)
Pages (from-to)4091-4103
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - Jan 1 2019

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Protein Biosynthesis
Pancreatic Neoplasms
Cell Survival
Oxygen
Glucose
Neoplasms
Adenocarcinoma
Hypoxia-Inducible Factor 1
Atlases
Growth
Cell Biology
Molecular Biology
Cell Death
Research Design
Therapeutics
Genome

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Huang, Chongbiao ; Li, Yang ; Li, Zengxun ; Xu, Yang ; Li, Na ; Ge, Yi ; Dong, Jie ; Chang, Antao ; Zhao, Tiansuo ; Wang, Xiuchao ; Wang, Hongwei ; Yang, Shengyu ; Xie, Keping ; Hao, Jihui ; Ren, He. / LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 13. pp. 4091-4103.
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title = "LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation",
abstract = "Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. Experimental Design: The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics. Results: LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expression was pivotal for tumor cells to survive in the oxygen- glucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth. Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygen- glucose deprivation conditions and is a promising therapeutic target for cancer treatment.",
author = "Chongbiao Huang and Yang Li and Zengxun Li and Yang Xu and Na Li and Yi Ge and Jie Dong and Antao Chang and Tiansuo Zhao and Xiuchao Wang and Hongwei Wang and Shengyu Yang and Keping Xie and Jihui Hao and He Ren",
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doi = "10.1158/1078-0432.CCR-18-3533",
language = "English (US)",
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Huang, C, Li, Y, Li, Z, Xu, Y, Li, N, Ge, Y, Dong, J, Chang, A, Zhao, T, Wang, X, Wang, H, Yang, S, Xie, K, Hao, J & Ren, H 2019, 'LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation', Clinical Cancer Research, vol. 25, no. 13, pp. 4091-4103. https://doi.org/10.1158/1078-0432.CCR-18-3533

LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation. / Huang, Chongbiao; Li, Yang; Li, Zengxun; Xu, Yang; Li, Na; Ge, Yi; Dong, Jie; Chang, Antao; Zhao, Tiansuo; Wang, Xiuchao; Wang, Hongwei; Yang, Shengyu; Xie, Keping; Hao, Jihui; Ren, He.

In: Clinical Cancer Research, Vol. 25, No. 13, 01.01.2019, p. 4091-4103.

Research output: Contribution to journalArticle

TY - JOUR

T1 - LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation

AU - Huang, Chongbiao

AU - Li, Yang

AU - Li, Zengxun

AU - Xu, Yang

AU - Li, Na

AU - Ge, Yi

AU - Dong, Jie

AU - Chang, Antao

AU - Zhao, Tiansuo

AU - Wang, Xiuchao

AU - Wang, Hongwei

AU - Yang, Shengyu

AU - Xie, Keping

AU - Hao, Jihui

AU - Ren, He

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. Experimental Design: The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics. Results: LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expression was pivotal for tumor cells to survive in the oxygen- glucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth. Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygen- glucose deprivation conditions and is a promising therapeutic target for cancer treatment.

AB - Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. Experimental Design: The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics. Results: LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expression was pivotal for tumor cells to survive in the oxygen- glucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth. Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygen- glucose deprivation conditions and is a promising therapeutic target for cancer treatment.

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