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Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro-survival capability via IGF-IR/PI3K/Akt signaling pathway activation

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Tumor Biology

Abstract

Despite rapid advances in the diagnostic and surgical procedures, hepatocellular carcinoma (HCC) remains one of the most difficult human malignancies to treat. This may be due to the chemoresistant behaviors of HCC. It is believed that acquired resistance could be overcome and improve the overall survival of HCC patients by understanding the mechanisms of chemoresistance in HCC. A stable HA22T cancer line, which is chronically resistant to a histone deacetylase inhibitor, was established. After comparing the molecular mechanism of apicidin-R HA22T cells to parental ones by Western blotting, cell cycle-regulated proteins did not change in apicidin-R cells, but apicidin-R cells were more proliferative and had higher tumor growth (wound-healing assay and nude mice xenograft model). Moreover, apicidin-R cells displayed increased levels of p-IGF-IR, p-PI3K, p-Akt, Bcl-xL, and Bcl-2 but also significantly inhibited the tumor suppressor PTEN protein and apoptotic pathways when compared to the parental strain. Therefore, the highly proliferative effect of apicidin-R HA22T cells was blocked by Akt knockdown. For all these findings, we believe that novel strategies to attenuate IGF-IR/PI3K/Akt signaling could overcome chemoresistance toward the improvement of overall survival of HCC patients.

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Authors and Affiliations

  1. Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan

    Hsi-Hsien Hsu

  2. Mackay Medicine, Nursing and Management College, Taipei, Taiwan

    Hsi-Hsien Hsu

  3. Graduate Institute of Basic Medical Science, China Medical University, 91 Hsueh-Shih Road, Taichung, 404, Taiwan, Republic of China

    Li-Hao Cheng, Ming-Cheng Chen, Nien-Hung Lee & Chih-Yang Huang

  4. Chinese Medicine Department, China Medical University Beigang Hospital, Beigang, Taiwan

    Tsung-Jung Ho

  5. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan

    Wei-Wen Kuo

  6. Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan

    Yueh-Min Lin

  7. Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan

    Yueh-Min Lin

  8. Puli Branch, Taichung Veterans General Hospital, Nantou, Taiwan

    Ming-Cheng Chen

  9. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

    Fuu-Jen Tsai & Chih-Yang Huang

  10. Department of Emergency Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan

    Kun-Hsi Tsai

  11. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan

    Kun-Hsi Tsai

  12. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    Chih-Yang Huang

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  1. Hsi-Hsien Hsu
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Correspondence to Chih-Yang Huang.

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Kun-Hsi Tsai and Chih-Yang Huang contributed equally to this paper.

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Hsu, HH., Cheng, LH., Ho, TJ. et al. Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro-survival capability via IGF-IR/PI3K/Akt signaling pathway activation. Tumor Biol. 35, 303–313 (2014). https://doi.org/10.1007/s13277-013-1041-3

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