Abstract
Hypoxia-induced activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway is frequently observed in solid tumors and is strongly associated with numerous pathophysiological processes, including the induction of epithelial-mesenchymal transition (EMT), which result in cancer progression and metastasis. Thus, inhibiting EMT through the suppression of the HIF-1 pathway may be a promising strategy for anticancer chemotherapy. Pien Tze Huang (PZH), a well-established traditional Chinese medicine has been prescribed for >450 years and has been used for centuries to clinically treat various types of human cancer. We previously reported that PZH suppresses multiple intracellular signaling pathways and thereby promotes the apoptosis of cancer cells and the inhibition of cell proliferation and tumor angiogenesis. In the present study, to further explore the mechanisms underlying the antitumor action of PZH, HCT-8 human colon carcinoma cells were cultured under hypoxic conditions and the effect of PZH on hypoxia-induced EMT was assessed. Hypoxia was found to induce EMT-associated morphological changes in HCT-8 cells, including loss of cell adhesion and the development of spindle-shaped fibroblastoid-like morphology. In addition, hypoxia was observed to reduce the expression of the epithelial marker E-cadherin, but increase that of the mesenchymal marker N-cadherin. In addition, hypoxia significantly enhanced HCT-8 cell migration and invasion and induced the activation of the HIF-1 pathway. However, treatment of the HCT-8 cells with PZH significantly inhibited the hypoxia-mediated EMT and HIF-1 signaling. These findings suggest that PZH inhibits hypoxia-induced cancer EMT through the suppression of the HIF-1 pathway, which may be one of the molecular mechanisms by which PZH exerts its antitumor activity.
Highlights
Hypoxia is a common characteristic of all rapidly growing solid tumors [1]
Treatment of the HCT‐8 cells with Pien Tze Huang (PZH) significantly inhibited the hypoxia‐mediated epithelial‐mesenchymal transition (EMT) and hypoxia‐inducible factor 1 (HIF‐1) signaling. These findings suggest that PZH inhibits hypoxia‐induced cancer EMT through the suppression of the hypoxia‐inducible factors (HIFs)‐1 pathway, which may be one of the molecular mechanisms by which PZH exerts its antitumor activity
HIF‐1α protein is continuously expressed, but rapidly degraded, as it is hydroxylated by prolyl hydroxylases (PHDs) at proline residues within the oxygen‐dependent degradation domain, which in turn mediates its interaction with the von Hippel‐Lindau tumor suppressor protein, eventually leading to HIF‐1α ubiquitination and degradation through a VHL‐dependent ubiquitin‐proteasome pathway [10,11,12]
Summary
Hypoxia is a common characteristic of all rapidly growing solid tumors [1]. Tumor hypoxia is caused by a number of factors, including inadequate blood supply due to abnormal tumor microvasculature, increased diffusion distances from the blood vessels to the tumor tissues and a reduced capacity of the blood to carry oxygen due to anemia [2]. While HIF‐1β is constitutively expressed in cells, HIF‐1α protein expression is dependent on intracellular oxygen concentration. CHEN et al: PIEN TZE HUANG INHIBITS HYPOXIA-INDUCED CANCER EMT hypoxic conditions, the O2‐dependent PHDs are inhibited, the interaction between HIF‐1α and pVHL is prevented. HIF‐1α overexpression is commonly found in numerous types of human cancer and is often associated with tumor progression and poor prognosis [16,17]. Through the process of EMT, carcinoma cells undergo migration and invasion, leading to cancer progression and metastasis [22]. To further elucidate the mechanism underlying the antitumor activity of PZH, the effect of PZH on EMT under hypoxia was investigated in a human colon carcinoma cell line
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