Abstract

Radiation therapy is a staple treatment for pancreatic cancer. However, owing to the intrinsic radioresistance of pancreatic cancer cells, radiation therapy often fails to increase survival of pancreatic cancer patients. Radiation impedes cancer cells by inducing DNA damage, which can activate cell cycle checkpoints. Normal cells possess both a G1 and G2 checkpoint. However, cancer cells are often defective in G1 checkpoint due to mutations/alterations in key regulators of this checkpoint. Accordingly, our results show that normal pancreatic ductal cells respond to ionizing radiation (IR) with activation of both checkpoints whereas pancreatic cancer cells respond to IR with G2/M arrest only. Overexpression/hyperactivation of Rac1 GTPase is detected in the majority of pancreatic cancers. Rac1 plays important roles in survival and Ras-mediated transformation. Here, we show that Rac1 also plays a critical role in the response of pancreatic cancer cells to IR. Inhibition of Rac1 using specific inhibitor and dominant negative Rac1 mutant not only abrogates IR-induced G2 checkpoint activation, but also increases radiosensitivity of pancreatic cancer cells through induction of apoptosis. These results implicate Rac1 signaling in the survival of pancreatic cancer cells following IR, raising the possibility that this pathway contributes to the intrinsic radioresistance of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)10251-10270
Number of pages20
JournalOncotarget
Volume5
Issue number21
DOIs
StatePublished - Jan 1 2014

Fingerprint

GTP Phosphohydrolases
Pancreatic Neoplasms
Ionizing Radiation
Survival
Radiotherapy
Radiation Tolerance
Cell- and Tissue-Based Therapy
Cell Cycle Checkpoints
DNA Damage
Neoplasms
Radiation
Apoptosis
Mutation

Keywords

  • ATM/ATR
  • Clonogenic survival
  • G2 checkpoint
  • Irradiation
  • Radiosensitivity

ASJC Scopus subject areas

  • Oncology

Cite this

Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation. / Yan, Ying; Hein, Ashley L.; Etekpo, Asserewou; Burchett, Katrina M.; Lin, Chi; Enke, Charles Arthur; Batra, Surinder Kumar; Cowan, Kenneth H; Ouellette, Michel M.

In: Oncotarget, Vol. 5, No. 21, 01.01.2014, p. 10251-10270.

Research output: Contribution to journalArticle

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