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Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells

 Kyung Hwan Kim  ;  Han Sang Kim  ;  Sang Cheol Kim  ;  DooA Kim  ;  Yong Bae Kim  ;  Hyun Cheol Chung  ;  Sun Young Rha 
 FRONTIERS IN ONCOLOGY, Vol.10 : 562284, 2020-09 
Journal Title
Issue Date
Akt ; MK-2206 ; gastric cancer ; gene signature ; radiosensitivity
Background: Despite the important role of radiotherapy in cancer treatment, a subset of patients responds poorly to treatment majorly due to radioresistance. Particularly the role of radiotherapy has not been established in gastric cancer (GC). Herein, we aimed to identify a radiosensitivity gene signature and to discover relevant targets to enhance radiosensitivity in GC cells.

Methods: An oligonucleotide microarray (containing 22,740 probes) was performed in 12 GC cell lines prior to radiation. A clonogenic assay was performed to evaluate the survival fraction at 2 Gy (SF2) as a surrogate marker for radiosensitivity. Genes differentially expressed (fold change > 6, q-value < 0.025) were identified between radiosensitive and radioresistant cell lines, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for validation. Gene set and pathway analyses were performed using Ingenuity Pathway Analysis (IPA).

Results: Radiosensitive (SF2 < 0.4) and radioresistant cell lines (SF2 ≥ 0.6) exhibited a marked difference in gene expression. We identified 68 genes that are differentially expressed between radiosensitive and radioresistant cell lines. The identified genes showed interactions via AKT, HIF1A, TGFB1, and TP53, and their functions were associated with the genetic networks associated with cellular growth and proliferation, cellular movement, and cell cycle. The Akt signaling pathway exhibited the highest association with radiosensitivity. Combinatorial treatment with MK-2206, an allosteric Akt inhibitor, and radiotherapy significantly increased cell death compared with radiotherapy alone in two radioresistant cell lines (YCC-2 and YCC-16).

Conclusion: We identified a GC-specific radiosensitivity gene signature and suggest that the Akt signaling pathway could serve as a therapeutic target for GC radiosensitization.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Kim, Yong Bae(김용배) ORCID logo https://orcid.org/0000-0001-7573-6862
Kim, Han Sang(김한상) ORCID logo https://orcid.org/0000-0002-6504-9927
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
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