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PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway.

ABSTRACT: Current lung cancer treatments are far from satisfactory; thus, finding novel treatment targets is crucial. We recently identified procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3), which is involved in fibrosis and tissue remodeling as a radioresistance-related protein in lung cancer cells; however, its mechanism is unclear. In this study, we designed human PLOD3-specific short interfering (si)RNAs and tested their effects on tumor growth inhibition in vitro and in vivo. PLOD3 knockdown overcame chemoresistance and decreased radioresistance by inducing caspase-3-dependent apoptosis in lung cancer cells. Furthermore, PLOD3 interacted with PKC? to activate caspase-2,4-dependent apoptosis through ER-stress-induced IRE1? activation and the downstream unfolded-protein response pathway. In a mouse xenograft model, PLOD3 knockdown promoted radiation-induced tumor growth inhibition, without side effects. Moreover, lung cancer patients with high PLOD3 expression showed poorer prognosis than those with low PLOD3 expression upon radiotherapy, suggesting that PLOD3 promotes tumor growth. Therefore, PLOD3 siRNA suppresses radioresistance and chemoresistance by inducing apoptosis and renders PLOD3 as a candidate lung cancer biomarker. PLOD3 gene therapy might enhance the efficacy of radiotherapy or chemotherapy in lung cancer patients.

SUBMITTER: Baek JH

PROVIDER: S-EPMC6377650 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway.

Baek Jeong-Hwa JH Yun Hong Shik HS Kwon Gyoo Taik GT Lee Janet J Kim Ju-Young JY Jo Yunhui Y Cho Jae-Min JM Lee Chang-Woo CW Song Jie-Young JY Ahn Jiyeon J Kim Jae-Sung JS Kim Eun Ho EH Hwang Sang-Gu SG

Cell death & disease 20190215 3

Current lung cancer treatments are far from satisfactory; thus, finding novel treatment targets is crucial. We recently identified procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3), which is involved in fibrosis and tissue remodeling as a radioresistance-related protein in lung cancer cells; however, its mechanism is unclear. In this study, we designed human PLOD3-specific short interfering (si)RNAs and tested their effects on tumor growth inhibition in vitro and in vivo. PLOD3 knockdow ...[more]

PMID: 30770789

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Project description:Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT. MATERIAL AND METHODS Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank). RESULTS The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival. CONCLUSION In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.

Dataset Information

PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway.

Publications

PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway.

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