TY - JOUR
T1 - Cationic antimicrobial peptide NRC-03 induces oral squamous cell carcinoma cell apoptosis via CypD-mPTP axis-mediated mitochondrial oxidative stress
AU - Hou, Dan
AU - Hu, Fengjun
AU - Mao, Yixin
AU - Yan, Liang
AU - Zhang, Yuhui
AU - Zheng, Zhichao
AU - Wu, Antong
AU - Forouzanfar, Tymour
AU - Pathak, Janak L.
AU - Wu, Gang
N1 - Funding Information: This study is supported by the High-End Foreign Expert Recruitment Plan of China (Grant No. G20200216024), National Natural Science Foundation of China (No. 82011530399 ), Key Research and Development Plan of Zhejiang Province of China (No. 2021C04013 ), High-level University Construction Funding of Guangzhou Medical University (02-412-B205002-1003017 and 06-410-2106035). Publisher Copyright: © 2022 The Authors
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Pleurocidin-family cationic antimicrobial peptide NRC-03 exhibits potent and selective cytotoxicity towards cancer cells. However, the anticancer effect of NRC-03 in oral squamous cell carcinoma (OSCC) and the molecular mechanism of NRC-03 induced cancer cell death is still unclear. This study focused to investigate mitochondrial oxidative stress-mediated altered mitochondrial function involved in NRC-03-induced apoptosis of OSCC cells. NRC-03 entered the OSCC cells more easily than that of normal cells and bound to mitochondria as well as the nucleus, causing cell membrane blebbing, mitochondria swelling, and DNA fragmentation. NRC-03 induced high oxygen consumption, reactive oxygen species (ROS) release, mitochondrial dysfunction, and apoptosis in OSCC cells. Non-specific antioxidant N-acetyl-L-cysteine (NAC), or mitochondria-specific antioxidant mitoquinone (MitoQ) alleviated NRC-03-induced apoptosis and mitochondrial dysfunction indicated that NRC-03 exerts a cytotoxic effect in cancer cells via inducing cellular and mitochondrial oxidative stress. Moreover, the expression of cyclophilin D (CypD), the key component of mitochondrial permeability transition pore (mPTP), was upregulated in NRC-03-treated cancer cells. Blockade of CypD by siRNA-mediated depletion or pharmacological inhibitor cyclosporine A (CsA) significantly suppressed NRC-03-induced mitochondrial oxidative stress, mitochondrial dysfunction, and apoptosis. NRC-03 also activated MAPK/ERK and NF-κB pathways. Importantly, intratumoral administration of NRC-03 inhibited the growth of CAL-27 cells-derived tumors on xenografted animal models. Taken together, our study indicates that NRC-03 induces apoptosis in OSCC cells via the CypD-mPTP axis mediated mitochondrial oxidative stress.
AB - Pleurocidin-family cationic antimicrobial peptide NRC-03 exhibits potent and selective cytotoxicity towards cancer cells. However, the anticancer effect of NRC-03 in oral squamous cell carcinoma (OSCC) and the molecular mechanism of NRC-03 induced cancer cell death is still unclear. This study focused to investigate mitochondrial oxidative stress-mediated altered mitochondrial function involved in NRC-03-induced apoptosis of OSCC cells. NRC-03 entered the OSCC cells more easily than that of normal cells and bound to mitochondria as well as the nucleus, causing cell membrane blebbing, mitochondria swelling, and DNA fragmentation. NRC-03 induced high oxygen consumption, reactive oxygen species (ROS) release, mitochondrial dysfunction, and apoptosis in OSCC cells. Non-specific antioxidant N-acetyl-L-cysteine (NAC), or mitochondria-specific antioxidant mitoquinone (MitoQ) alleviated NRC-03-induced apoptosis and mitochondrial dysfunction indicated that NRC-03 exerts a cytotoxic effect in cancer cells via inducing cellular and mitochondrial oxidative stress. Moreover, the expression of cyclophilin D (CypD), the key component of mitochondrial permeability transition pore (mPTP), was upregulated in NRC-03-treated cancer cells. Blockade of CypD by siRNA-mediated depletion or pharmacological inhibitor cyclosporine A (CsA) significantly suppressed NRC-03-induced mitochondrial oxidative stress, mitochondrial dysfunction, and apoptosis. NRC-03 also activated MAPK/ERK and NF-κB pathways. Importantly, intratumoral administration of NRC-03 inhibited the growth of CAL-27 cells-derived tumors on xenografted animal models. Taken together, our study indicates that NRC-03 induces apoptosis in OSCC cells via the CypD-mPTP axis mediated mitochondrial oxidative stress.
KW - Cell apoptosis
KW - Cyclophilin D
KW - NRC-03
KW - Oral squamous cell carcinoma
KW - Oxidative stress
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U2 - https://doi.org/10.1016/j.redox.2022.102355
DO - https://doi.org/10.1016/j.redox.2022.102355
M3 - Article
C2 - 35660629
SN - 2213-2317
VL - 54
SP - 1
EP - 19
JO - Redox Biology
JF - Redox Biology
M1 - 102355
ER -