Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Hui Wen Chiu, Shu Wen Lin, Li Ching Lin, Yung Ho Hsu, Yuh Feng Lin, Sheng Yow Ho, Yuan Hua Wu, Ying Jan Wang

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Ninety percent of human pancreatic cancer is characterized by activating K-RAS mutations. TRAF6 is an oncogene that plays a vital role in K-RAS-mediated oncogenesis. We investigated the synergistic effect of combining ionizing radiation (IR) and proteasome inhibitor (MG132). Furthermore, following combined treatment with IR and MG132, we analyzed the expression of TRAF6 and the mechanism of human pancreatic cancer cell death in vitro and in an orthotopic pancreatic cancer mouse model. The combined treatment groups displayed synergistic cell killing effects and induced endoplasmic reticulum stress in human pancreatic cancer cells. The combined treatment groups were characterized by enhanced cytotoxicity, which resulted from increased autophagy induction through the inhibition of TRAF6. Significantly reduced cytotoxicity was observed following MG132 and IR treatment of MIA PaCa-2 cells pre-treated with 3-MA (an autophagy inhibitor). Down-regulation of TRAF6 led to a significant increase in apoptosis and autophagy. In an orthotopic xenograft model of SCID mice, combination MG132 and IR therapy resulted in a significant increase in the tumor growth delay time and a decreased tumor tissue expression of TRAF6. IR combined with a proteasome inhibitor or TRAF6 inhibition could represent a new therapeutic strategy for human pancreatic cancer.

Original languageEnglish
Pages (from-to)229-239
Number of pages11
JournalCancer Letters
Volume365
Issue number2
DOIs
Publication statusPublished - Sep 1 2015

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TNF Receptor-Associated Factor 6
Proteasome Inhibitors
Radiation Effects
Autophagy
Pancreatic Neoplasms
Ionizing Radiation
Down-Regulation
Therapeutics
Endoplasmic Reticulum Stress
SCID Mice
Oncogenes
Heterografts
Neoplasms
Carcinogenesis
Cell Death
Radiotherapy
Apoptosis
Mutation
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Growth

Keywords

  • Autophagy
  • Endoplasmic reticulum stress
  • Pancreatic cancer
  • Proteasome inhibitor
  • Radiation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. / Chiu, Hui Wen; Lin, Shu Wen; Lin, Li Ching; Hsu, Yung Ho; Lin, Yuh Feng; Ho, Sheng Yow; Wu, Yuan Hua; Wang, Ying Jan.

In: Cancer Letters, Vol. 365, No. 2, 01.09.2015, p. 229-239.

Research output: Contribution to journalArticle

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