Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.

Xiaolei Li, Zhiqiang Wu, Xiaojing An, Qian Mei, Miaomiao Bai, Leena Hanski, Xiang Li, Tero Ahola, Weidong Han

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKK beta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.
Original languageEnglish
Article numbere27301
JournaleLife
Volume6
Number of pages34
ISSN2050-084X
DOIs
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine
  • 317 Pharmacy
  • NF-KAPPA-B
  • PROTEIN-KINASE PKR
  • ESTROGEN-RECEPTOR-ALPHA
  • COLON-CANCER
  • ADJUVANT CHEMOTHERAPY
  • GENOTOXIC STRESS
  • DRUG-RESISTANCE
  • BREAST-CANCER
  • ACTIVATION
  • RNA

Cite this

Li, Xiaolei ; Wu, Zhiqiang ; An, Xiaojing ; Mei, Qian ; Bai, Miaomiao ; Hanski, Leena ; Li, Xiang ; Ahola, Tero ; Han, Weidong. / Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy. In: eLife. 2017 ; Vol. 6.
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title = "Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.",
abstract = "Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKK beta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.",
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author = "Xiaolei Li and Zhiqiang Wu and Xiaojing An and Qian Mei and Miaomiao Bai and Leena Hanski and Xiang Li and Tero Ahola and Weidong Han",
year = "2017",
doi = "10.7554/eLife.27301",
language = "English",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "ELIFE SCIENCES PUBLICATIONS LTD",

}

Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy. / Li, Xiaolei ; Wu, Zhiqiang; An, Xiaojing; Mei, Qian; Bai, Miaomiao; Hanski, Leena ; Li, Xiang; Ahola, Tero ; Han, Weidong.

In: eLife, Vol. 6, e27301, 2017.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.

AU - Li, Xiaolei

AU - Wu, Zhiqiang

AU - An, Xiaojing

AU - Mei, Qian

AU - Bai, Miaomiao

AU - Hanski, Leena

AU - Li, Xiang

AU - Ahola, Tero

AU - Han, Weidong

PY - 2017

Y1 - 2017

N2 - Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKK beta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.

AB - Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKK beta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.

KW - 3111 Biomedicine

KW - 317 Pharmacy

KW - NF-KAPPA-B

KW - PROTEIN-KINASE PKR

KW - ESTROGEN-RECEPTOR-ALPHA

KW - COLON-CANCER

KW - ADJUVANT CHEMOTHERAPY

KW - GENOTOXIC STRESS

KW - DRUG-RESISTANCE

KW - BREAST-CANCER

KW - ACTIVATION

KW - RNA

U2 - 10.7554/eLife.27301

DO - 10.7554/eLife.27301

M3 - Article

VL - 6

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e27301

ER -