title: GDC-0980-induced apoptosis is enhanced by autophagy inhibition in human pancreatic cancer cells.
abstract: Pancreatic cancer remains fatal to the fast majority of affected patients. Activation of phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway plays an important role in pancreatic cancer progression and chemo-resistance. In the present study, we examined the activity of GDC-0980, a novel class I PI3K/mTOR kinase inhibitor, against pancreatic cancer cells in vitro. GDC-0980 inhibited AKT-mTOR activation and pancreatic cancer cell (PANC-1 and Capan-1 lines) survival. In both cancer cell lines, GDC-0980 simultaneously activated apoptosis and autophagy, the latter was detected by p62 degradation, Beclin-1 upregulation and light chain 3B (LC3B) conversion from a cytosolic (LC3B-I) to a membrane-bound (LC3B-II) form. Autophagy inhibitors including 3-methyladenine, hydroxychloroquine, NH4Cl and bafilomycin A1 enhanced apoptosis and cytotoxicity by GDC-0980, such an effect was reversed by caspase inhibitors (z-VAD-FMK and z-ITED-FMK). Furthermore, knockdown of LC3B or Beclin-1 through siRNA increased GDC-0980-induced anti-pancreatic cancer cell activity. Thus, inhibition of autophagy sensitizes GDC-0980-induced anti-pancreatic cancer activity, suggesting a novel therapeutic strategy for GDC-0980 sensitization.
authors.affiliation: Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Tang
authors.affiliation: Department of Hepatobiliary Surgery, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu Province, China.
authors.forename: Tu
authors.initials: T
authors.lastname: Dai
authors.affiliation: Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Wu-Jun
authors.initials: WJ
authors.lastname: Xiong
authors.affiliation: Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Ming-Zheng
authors.initials: MZ
authors.lastname: Xu
authors.affiliation: Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Xu-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China.
authors.forename: Qing-He
authors.initials: QH
authors.lastname: Tang
authors.affiliation: Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China. Electronic address: bobo126red@126.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China. Electronic address: mingsumd@sina.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D019086:Bridged Bicyclo Compounds, Heterocyclic; C502070:MAP1LC3B protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011743:Pyrimidines
keywords: Autophagy and chemo-sensitization; GDC-0980; PI3K–AKT–mTOR; Pancreatic cancer