Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy

Kwan Hwa Chi, Yu Shan Wang, Yi Chun Huang, Hsin Chien Chiang, Mau Shin Chi, Chau Hwa Chi, Hsin Ell Wang, Shang Jyh Kao

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

While combined chemotherapy (CT) with an autophagy inducer and an autophagy inhibitor appears paradoxical, it may provide a more effective perturbation of autophagy pathways. We used two dissimilar cell lines to test the hypothesis that autophagy is the common denominator of cell fate after CT. HA22T cells are characterized by CT-induced apoptosis and use autophagy to prevent cell death, while Huh7.5.1 cells exhibit sustained autophagic morphology after CT. Combined CT and rapamycin treatment resulted in a better combination index (CI) in Huh7.5.1 cells than combined CT and chloroquine, while the reverse was true in HA22T cells. The combination of 3 drugs (triplet drug treatment) had the best CI. After triplet drug treatment, HA22T cells switched from protective autophagy to mitochondrial membrane permeabilization and endoplasmic reticulum stress response-induced apoptosis, while Huh7.5.1 cells intensified autophagic lethality. Most importantly, both cell lines showed activation of Akt after CT, while the triplet combination blocked Akt activation through inhibition of phospholipid lipase D activity. This novel finding warrants further investigation as a broad chemosensitization strategy.

Original languageEnglish
Pages (from-to)58075-58088
Number of pages14
JournalOncotarget
Volume7
Issue number36
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Autophagy
  • Chemosensitization
  • Chloroquine
  • Rapamycin
  • Synthetic lethality

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Chi, K. H., Wang, Y. S., Huang, Y. C., Chiang, H. C., Chi, M. S., Chi, C. H., Wang, H. E., & Kao, S. J. (2016). Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy. Oncotarget, 7(36), 58075-58088. https://doi.org/10.18632/oncotarget.10873