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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 PKCδ to activate caspase-2,4-dependent apoptosis through ER-stress-induced IRE1α 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.

Author information

Baek JH1,2, Yun HS1, Kwon GT1, Lee J1, Kim JY1, Jo Y1, Cho JM1, Lee CW2, Song JY1, Ahn J1, Kim JS1, Kim EH3, Hwang SG4.
1
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, 01812, Korea.
2
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, Korea.
3
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, 01812, Korea. eh140149@kirams.re.kr.
4
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, 01812, Korea. sgh63@kcch.re.kr.