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Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo.

ABSTRACT: Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1? and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1?, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.

SUBMITTER: Takeda D

PROVIDER: S-EPMC4079455 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo.

Takeda Daisuke D Hasegawa Takumi T Ueha Takeshi T Imai Yusuke Y Sakakibara Akiko A Minoda Masaya M Kawamoto Teruya T Minamikawa Tsutomu T Shibuya Yasuyuki Y Akisue Toshihiro T Sakai Yoshitada Y Kurosaka Masahiro M Komori Takahide T

PloS one 20140702 7

Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, includi ...[more]

PMID: 24988190

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Project description:Mitochondria play an essential role in cellular energy metabolism and apoptosis. Previous studies have demonstrated that decreased mitochondrial biogenesis is associated with cancer progression. In mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) regulates the activities of multiple nuclear receptors and transcription factors involved in mitochondrial proliferation. Previously, we showed that overexpression of PGC-1α leads to mitochondrial proliferation and induces apoptosis in human malignant fibrous histiocytoma (MFH) cells in vitro. We also demonstrated that transcutaneous application of carbon dioxide (CO(2)) to rat skeletal muscle induces PGC-1α expression and causes an increase in mitochondrial proliferation. In this study, we utilized a murine model of human MFH to determine the effect of transcutaneous CO(2) exposure on PGC-1α expression, mitochondrial proliferation and cellular apoptosis. PGC-1α expression was evaluated by quantitative real-time PCR, while mitochondrial proliferation was assessed by immunofluorescence staining and the relative copy number of mitochondrial DNA (mtDNA) was assessed by real-time PCR. Immunofluorescence staining and DNA fragmentation assays were used to examine mitochondrial apoptosis. We also evaluated the expression of mitochondrial apoptosis related proteins, such as caspases, cytochorome c and Bax, by immunoblot analysis. We show that transcutaneous application of CO(2) induces PGC-1α expression, and increases mitochondrial proliferation and apoptosis of tumor cells, significantly reducing tumor volume. Proteins involved in the mitochondrial apoptotic cascade, including caspase 3 and caspase 9, were elevated in CO(2) treated tumors compared to control. We also observed an enrichment of cytochrome c in the cytoplasmic fraction and Bax protein in the mitochondrial fraction of CO(2) treated tumors, highlighting the involvement of mitochondria in apoptosis. These data indicate that transcutaneous application of CO(2) may represent a novel therapeutic tool in the treatment of human MFH.

Dataset Information

Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo.

Publications

Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo.

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