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Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Haptoglobin (Hp) is an acute-phase protein secreted by the liver; its concentration increases rapidly during infection, inflammation, and tumor formation. It has been reported that the level of Hp α alleles is altered in the serum of patients with head and neck squamous cell carcinoma (HNSCC), and the cellular level of Hp is strongly associated with the recurrence rate of HNSCC in patients. In the present study, the regulated mechanism of Hp expression was explored.Materials and Methods: We first identified the genetic polymorphism of Hp by PCR. The expression of Hp isoforms was determined through Western Blotting analysis. With the JAK specific inhibitors, the clear regulation mechanism was explored.Results: We observed that Hp exhibited variant polymorphisms in different cells. We found that interleukin-6 (IL-6) induced the expressions of Hp α2 in FaDu cells, and Hp α1 in SCC4 cells. Furthermore, the phosphorylated level of STAT3 was elevated with IL-6 treatment. Janus-associated kinase 2 (JAK-2) inhibitor, WP1066, reduced the phosphorylation of STAT3 after IL-6 induction, leading to the downregulation of Hp expression.Conclusions: The expression of Hp was increased via IL-6 induction through the activation of the transcription factor STAT3 in HNSCC cells. [ABSTRACT FROM AUTHOR]

Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12- O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-B (NF-B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-B nuclear translocation through IB. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies. [ABSTRACT FROM AUTHOR]