Transcutaneous Carbon Dioxide Induces Mitochondrial Apoptosis and Suppresses Metastasis of Oral Squamous Cell Carcinoma In Vivo

Takeda, Daisuke; Hasegawa, Takumi; Ueha, Takeshi; Imai, Yusuke; Sakakibara, Akiko; Minoda, Masaya; Kawamoto, Teruya; Minamikawa, Tsutomu; Shibuya, Yasuyuki; Akisue, Toshihiro; Sakai, Yoshitada; Kurosaka, Masahiro; Komori, Takahide

doi:10.1371/journal.pone.0100530

Cited by 24 publications

(66 citation statements)

References 38 publications

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“…Given this evidence, we can infer that the CO 2 -mediated reduction in EPO is likely due at least in part to HIF suppression rather than the effects of systemic reoxygenation. Recent works that have demonstrated the ability of 100% CO 2 to suppress hypoxic responses in tumors are supportive of our findings (45)(46)(47)(48). Compared with room air controls, 100% CO 2 was found to reduce HIF-1␣ stabilization and VEGF mRNA expression in mice implanted with a malignant human histiocytoma.…”

Section: Discussionsupporting

confidence: 90%

“…Compared with room air controls, 100% CO 2 was found to reduce HIF-1␣ stabilization and VEGF mRNA expression in mice implanted with a malignant human histiocytoma. 100% CO 2 also decreased tumor growth while augmenting the effectiveness of chemotherapeutic doxorubicin treatment (45)(46)(47)(48). Suppression of the HIF pathway by hypercapnia is of clinical significance given the occurrence of hypoxia and its sequelae in numerous diseases.…”

Section: Discussionmentioning

confidence: 99%

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Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-␣ protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O 2 -dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-␣ protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO 2 . Bafilomycin A1, a specific inhibitor of vacuolar-type H ؉ -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-␣ protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-␣ subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.Current atmospheric CO 2 levels are relatively low when compared with those recorded throughout the natural history of the planet (1). Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2-4).Because O 2 consumption is coupled to CO 2 production, an intimate inverse relationship exists between the levels of these gases in cells and tissues. Furthermore, O 2 and CO 2 levels may become perturbed during certain pathophysiologic states (3, 5). Hypoxia and hypercapnia can co-occur in respiratory disorders such as obstructive sleep apnea syndrome, pneumonia, and chronic obstructive pulmonary disease (6, 7). In acute lung injury hypoxia may arise, whereas permissive hypercapnia is often tolerated as a protective ventilatory strategy in patients presenting with this disorder (8, 9). Hypercapnia and hypoxia also influence inflammatory processes (10 -12). During inflammation, oxygen consumption is significantly elevated, leading to tissue hypoxia. It is likely that this also has consequences for tissue CO 2 levels (3, 11). HIF 8 (which comprises the HIF-1, HIF-2, and HIF-3 isoforms) is the master transcriptional regulator of the cellular response to hypoxia (13). Canonical HIF degradation relies on the activity of O 2 -dependent prolyl hydroxylases 1-3 (14). In normoxia, prolyl hydroxylases enzymatically modify HIF-␣ subunits on proli...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…15 All TaqMan probes and primer sets were custom-made and purchased from Applied Biosystems. Total RNA was extracted from both tissues using an RNeasy Mini Kit (Qiagen, Valencia, CA).…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

“…15 Signals were developed as a brown reaction product using peroxidase substrate 3 0 ,3 0diaminobenzidine (Nichirei Bioscience, Tokyo, Japan). We prepared formalin-fixed and paraffin-embedded tissue sections, which were incubated overnight at 48C with the following primary antibodies in Can Get Signal Immunostain Solution A (Toyobo, Osaka, Japan); mouse anti-PGC-1a antibody (1:50; Abnova, Taipei, Taiwan); and mouse anti-TFAM antibody (1:50; Abnova).…”

Section: Immunohistochemical and Immunofluorescence Stainingmentioning

confidence: 99%