IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells

Satoru Osuka, Oltea Sampetrean, Takatsune Shimizu, Isako Saga, Nobuyuki Onishi, Eiji Sugihara, Jun Okubo, Satoshi Fujita, Shingo Takano, Akira Matsumura, Hideyuki Saya

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

Original languageEnglish
Pages (from-to)627-640
Number of pages14
JournalStem Cells
Volume31
Issue number4
DOIs
Publication statusPublished - 2013 Apr

Fingerprint

IGF Type 1 Receptor
Glioma
Stem Cells
Radiation
Neoplastic Stem Cells
Up-Regulation
Radiation Tolerance
Extracellular Signal-Regulated MAP Kinases
DNA Repair
Down-Regulation
Recurrence
Population
Neoplasms

Keywords

  • Cancer stem cell
  • Forkhead box O
  • Glioblastoma
  • Insulin-like growth factor 1
  • Radioresistance

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. / Osuka, Satoru; Sampetrean, Oltea; Shimizu, Takatsune; Saga, Isako; Onishi, Nobuyuki; Sugihara, Eiji; Okubo, Jun; Fujita, Satoshi; Takano, Shingo; Matsumura, Akira; Saya, Hideyuki.

In: Stem Cells, Vol. 31, No. 4, 04.2013, p. 627-640.

Research output: Contribution to journalArticle

Osuka, S, Sampetrean, O, Shimizu, T, Saga, I, Onishi, N, Sugihara, E, Okubo, J, Fujita, S, Takano, S, Matsumura, A & Saya, H 2013, 'IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells', Stem Cells, vol. 31, no. 4, pp. 627-640. https://doi.org/10.1002/stem.1328
Osuka, Satoru ; Sampetrean, Oltea ; Shimizu, Takatsune ; Saga, Isako ; Onishi, Nobuyuki ; Sugihara, Eiji ; Okubo, Jun ; Fujita, Satoshi ; Takano, Shingo ; Matsumura, Akira ; Saya, Hideyuki. / IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. In: Stem Cells. 2013 ; Vol. 31, No. 4. pp. 627-640.
@article{5287851eec1143128e7e89b4849a4438,
title = "IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells",
abstract = "Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.",
keywords = "Cancer stem cell, Forkhead box O, Glioblastoma, Insulin-like growth factor 1, Radioresistance",
author = "Satoru Osuka and Oltea Sampetrean and Takatsune Shimizu and Isako Saga and Nobuyuki Onishi and Eiji Sugihara and Jun Okubo and Satoshi Fujita and Shingo Takano and Akira Matsumura and Hideyuki Saya",
year = "2013",
month = "4",
doi = "10.1002/stem.1328",
language = "English",
volume = "31",
pages = "627--640",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells

AU - Osuka, Satoru

AU - Sampetrean, Oltea

AU - Shimizu, Takatsune

AU - Saga, Isako

AU - Onishi, Nobuyuki

AU - Sugihara, Eiji

AU - Okubo, Jun

AU - Fujita, Satoshi

AU - Takano, Shingo

AU - Matsumura, Akira

AU - Saya, Hideyuki

PY - 2013/4

Y1 - 2013/4

N2 - Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

AB - Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

KW - Cancer stem cell

KW - Forkhead box O

KW - Glioblastoma

KW - Insulin-like growth factor 1

KW - Radioresistance

UR - http://www.scopus.com/inward/record.url?scp=84875767442&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875767442&partnerID=8YFLogxK

U2 - 10.1002/stem.1328

DO - 10.1002/stem.1328

M3 - Article

C2 - 23335250

AN - SCOPUS:84875767442

VL - 31

SP - 627

EP - 640

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 4

ER -