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C. Xie
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.10 - CAY10603, a Novel Inhibitor of HDAC6, Suppresses Non-Small Cell Lung Cancer Cell Growth via Modulating Both Autophagy and Apoptosis Pathways (ID 1305)
11:40 - 11:45 | Author(s): C. Xie
- Abstract
Background:
Histone deacetylase 6 (HDAC6) is a key regulator of many signaling pathways linked to cancer. But unlike other HDACs, inhibition of HDAC6 is believed not to be associated with severe toxicity, making HDAC6 a possible cancer treatment target. Overexpression of HDAC6 has been observed in many types of cancer including NSCLC. Knockdown of HDAC6 sensitizes NSCLC cell lines to chemotherapy induced cell apoptosis. Apoptosis and autophagy are the 2 cellular processes likely to alter efficacy of a therapeutic agent. Autophagy confers resistance to chemotherapy by inhibiting apoptosis. HDAC6 controls autophagosome maturation and is essential for autophagy. CAY10603 is a potent and selective inhibitor of HDAC6. Therefore, inhibition of HDAC6 by CAY10603 could be a promising strategy to treat NSCLC by targeting both apoptosis and autophagy pathways.
Methods:
We evaluated the effect of CAY10603 alone or in combination with autophagy inhibition on cell proliferation, apoptosis and autophagy in two human NSCLC cell lines, A549 and H460. Pharmacological (chloroquine or bafilomycin-A1) or genetic (knockdown of ATG5 or Beclin1 with shRNA) approaches were utilized to block autophagy. Cell proliferation of untreated or drug-treated cells was measured by CCK8 assay. Percentage of apoptotic cells was measured using PE-conjugated Annexin V with a flow cytometer. Autophagy was determined by conversion of LC3I to LC3II and p62 degradation using Western blot.
Results:
CAY10603 inhibits NSCLC cell proliferation and induces apoptosis. CAY10603 also inhibits HDAC6 dependent basal autophagy and activates the PI3K-Akt-mTOR pathway. Meanwhile, HDAC6 independent autophagy exists in NSCLC cells and confers resistance to CAY10603. Cotreatment with chloroquine or bafilomycin-A1 promotes the autophagy inhibition, cell growth suppression and apoptosis induction of NSCLC cells compared to CAY10603 alone. Knockdown of ATG5 or Beclin1 by shRNA also increased CAY10603-induced cytotoxicity in above NSCLC cells.
Conclusion:
Our results indicate that CAY10603 may be a promising agent for the treatment of NSCLC by modulating autophagy and apoptosis pathways. Furthermore, the combination of CAY10603 with classical autophagy inhibitors represents a promising therapeutic strategy that warrants further clinical evaluation in NSCLC.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-106 - ATG7-Dependent Autophagy May Not Be Involved in Prognosis of Human NSCLCÂ (ID 1310)
09:30 - 09:30 | Author(s): C. Xie
- Abstract
Background:
Autophagy, one of two major intracellular degradation pathways, plays a critical role in energy homeostasis and the quality control of macromolecules and intracellular organelles. Autophagy plays a role in the various stages of tumorigenesis. However, the role of autophagy in cancer seems complex. Autophagy confers both pro- and anti-tumourigenic roles, depending on the cellular and environmental context. Autophagy related gene 7 (ATG7) is an essential autophagy gene. Previous studies showed that ATG7-dependent autophagy represses early oncogenesis but accelerating tumour progression in mouse lung cancer models. However, the expression of ATG7 and its correlation with prognosis of human lung cancer have not been reported.
Methods:
In Cohort 1, we analyzed 41 patients with non-small-cell-lung cancer who had undergone surgery from June 2013 through December 2013. Expression levels of ATG7 in the tumor tissues and the adjacent normal tissues were examined by immunohistochemistry. We then sought to find the relationship between the expression of ATG7 and the overall survival of NSCLC. In Cohort 2, we screened surgery sample library in Department of pathology, Zhongnan Hospital of Wuhan University for NSCLC patients sample from 2010 to 2011. None of the patients underwent radiotherapy or chemotherapy before surgery. Tissue samples of 76 included patients were obtained with the assistant of work staff in that department. Baseline characteristics were collected mainly by consulting archived medical records and the same staging system was referred to anew classify stage. Follow-up was completed within 2 months mainly through telephone contact. 13 patients were excluded from this study because of contact loss. The samples of the rest with a median age of 60 (range 37-79) were submitted for further immunohistochemical analysis and survival data analysis were conducted. Immunohistochemistry was performed by a well-trained pathological technicist.
Results:
In Cohort 1, ATG7 protein was detected mainly in the cytoplasm of tumor cells. Positive staining was identified in 26 (63.4%) tumor tissue samples while only 9 (9.8%) normal lung tissue samples were considered as positive. Chi-square test revealed a significant difference (p<0.01). In Cohort 2, Patients with no ATG7 expression had a median survival time of 17.5 months (95%CI, 11.9-23.1 months) while patients with positive ATG7 expression had the same survival time of 17.5 months (95% CI, 11.3-23.7 months). No significant difference was noticed (p=0.199).
Conclusion:
Differential expression of ATG7 between cancer cells and normal tissues indicates that ATG7 is related to early oncogenesis of NSCLC. However, different from the results obstained from mouse models, ATG7 expression is not correlated with prognosis of human NSCLC.
