Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy
| Autor: | Mau Shin Chi, Hsin Ell Wang, Hsin Chien Chiang, Shang Jyh Kao, Yi Chun Huang, Chau-Hwa Chi, Kwan Hwa Chi, Yu Shan Wang |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine autophagy Programmed cell death medicine.medical_treatment Apoptosis Mice SCID Synthetic lethality chloroquine Mice 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols Phospholipase D medicine Animals Humans Vinca Alkaloids Protein kinase B Cell Proliferation Sirolimus Chemotherapy rapamycin business.industry TOR Serine-Threonine Kinases Autophagy Drug Synergism Combination chemotherapy Endoplasmic Reticulum Stress chemosensitization Xenograft Model Antitumor Assays synthetic lethality 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mitochondrial Membranes Cancer cell Immunology Cancer research Reactive Oxygen Species business Proto-Oncogene Proteins c-akt Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Kwan-Hwa Chi 1, 2, 4 , Yu-Shan Wang 1, 3 , Yi-Chun Huang 3 , Hsin-Chien Chiang 3 , Mau-Shin Chi 1 , Chau-Hwa Chi 4 , Hsin-Ell Wang 2 , Shang-Jyh Kao 5 1 Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 2 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 3 Department of Research and Development, JohnPro Biotech Inc., Taipei, Taiwan 4 Institute of Veterinary Clinical Science, National Taiwan University, Taipei, Taiwan 5 Division of Pulmonary Medicine, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan Correspondence to: Kwan-Hwa Chi, email: M006565@ms.skh.org.tw Shang-Jyh Kao, email: M001002@ms.skh.org.tw 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. |
| Databáze: | OpenAIRE |
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