Oncotarget

Research Papers:

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 and Shang-Jyh Kao

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Oncotarget. 2016; 7:58075-58088. https://doi.org/10.18632/oncotarget.10873

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Abstract

Kwan-Hwa Chi1,2,4, Yu-Shan Wang1,3, Yi-Chun Huang3, Hsin-Chien Chiang3, Mau-Shin Chi1, Chau-Hwa Chi4, Hsin-Ell Wang2, Shang-Jyh Kao5

1Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

2Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan

3Department of Research and Development, JohnPro Biotech Inc., Taipei, Taiwan

4Institute of Veterinary Clinical Science, National Taiwan University, Taipei, Taiwan

5Division of Pulmonary Medicine, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

Correspondence to:

Kwan-Hwa Chi, email: [email protected]

Shang-Jyh Kao, email: [email protected]

Keywords: autophagy, rapamycin, chloroquine, chemosensitization, synthetic lethality

Received: January 25, 2016     Accepted: July 09, 2016     Published: July 28, 2016

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.


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