CuZnSOD and MnSOD inhibit metabolic stress-induced necrosis and multicellular tumour spheroid growth.
CuZnSOD and MnSOD have been shown to exert tumour suppressive activities; however, their exact molecular mechanism is still unclear. We investigated the molecular mechanism underlying the tumour suppressive activities of CuZnSOD and MnSOD using multicellular tumour spheroid (MTS), an in vitro tumour model. Overexpression of CuZnSOD and MnSOD significantly suppressed the growth of A549 and MCF-7 MTS, supporting a critical role(s) of reactive oxygen species (ROS) in tumour growth. In solid tumours, ROS is produced by metabolic stress due to insufficient oxygen and glucose supply and induces necrosis that is known to promote tumour progression by releasing the proinflammatory cytokine HMGB1. We observed that CuZnSOD and MnSOD overexpression prevents metabolic stress-induced necrosis and HMGB1 release by inhibiting mitochondrial ROS and intracellular O2- production in response to glucose depletion in two dimensional cell culture. CuZnSOD and MnSOD overexpression also significantly repressed the occurrence of necrosis that was observed during MTS culture. In human tumour tissues including lung pulmonary adenocarcinoma, CuZnSOD and MnSOD expression was detected in the para-necrotic region that was identified by the expression of a hypoxic marker carbonic anhydrase (CA) IX. These results suggest that CuZnSOD and MnSOD may suppress tumour growth through inhibiting metabolic stress-induced necrosis and HMGB1 release via inhibiting metabolic stress-induced mitochondrial ROS production.
Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea.
Su Yeon
SY
Lee
Hyun Min
HM
Jeon
Cho Hee
CH
Kim
Eui Kyong
EK
Jeong
Min Kyung
MK
Ju
Song Yi
SY
Park
Seung Youn
SY
Jung
Yung Jin
YJ
Kim
Sung-Chul
SC
Lim
Song Iy
SI
Han
Ho Sung
HS
Kang
D018929:Cell Culture Techniques; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology*; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
D024243:HMGB1 Protein; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase