title: Oncolytic newcastle disease virus triggers cell death of lung cancer spheroids and is enhanced by pharmacological inhibition of autophagy.
abstract: Lung cancer stem cells (CSCs) have recently been isolated from lung cancer patient samples and have been reported to be responsible for tumor initiation, treatment resistance and tumor recurrence. We have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW) induces apoptosis in drug-resistant lung cancer cells. However, how NDV exerts its oncolytic effect on lung CSCs remains to be investigated. Here we show that NDV/FMW replicates in, and lyses CSC-enriched lung cancer spheroids and inhibits the 3D growth potential of lung cancer spheroid and agar colonies. We demonstrate that NDV/FMW triggers caspase-dependent apoptosis in lung cancer spheroids as shown by increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage. Notably, NDV/FMW infection results in the degradation of microtubule-associated protein 1 light chain 3 (LC3) II and P62, two hallmarks of autophagy maturation, indicating that NDV/FMW promotes autophagy flux in lung cancer cell spheroids. This was further confirmed by the appearance of an increased number of double-membrane vesicles as detected by transmission electron microscopy. We also show that NDV/FMW promotes autophagy degradation in lung cancer spheroids via inhibition of the AKT/mTOR pathway. In addition, treatment of spheroids with the autophagy inhibitor, chloroquine increases NDV/FMW-induced cytotoxicity. Collectively, our data show that oncolytic NDV/FMW may be a potential strategy in targeting lung CSCs.
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University Dalian 116044, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Hu
authors.affiliation: Biotherapy Research Center, Liaoning Cancer Hospital & Institute 44 Xiaoheyan Road, Shenyang 110042, China.
authors.forename: Sulan
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Medical Image, Liaoning Cancer Hospital 44 Xiaoheyan Road, Shenyang 110042, China.
authors.forename: Tianpeng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Biotherapy Research Center, Liaoning Cancer Hospital & Institute 44 Xiaoheyan Road, Shenyang 110042, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University Dalian 116044, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Jiang
authors.affiliation: College of Bioscience and Biotechnology, Yangzhou University 48 East, Wenhui Road, Yangzhou 225009, China.
authors.forename: Guibin
authors.initials: G
authors.lastname: Lin
authors.affiliation: School of Veterinary Medicine, Yangzhou University 48 East, Wenhui Road, Yangzhou 225009, Jiangsu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences St. James's Hospital & Trinity College Dublin Dublin, Ireland.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Barr
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, Dalian Medical University Dalian 116044, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: Biotherapy Research Center, Liaoning Cancer Hospital & Institute 44 Xiaoheyan Road, Shenyang 110042, China.
authors.forename: Guirong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University Dalian 116044, China.
authors.forename: Songshu
authors.initials: S
authors.lastname: Meng
keywords: Newcastle disease virus; apoptosis; autophagy; cancer stem cell; lung cancer; spheroid