Radioresistance is a major factor leading to the failure of radiotherapy and poor prognosis in tumor patients. Following the application of radiotherapy, the activity of various metabolic pathways considerably changes, which may result in the development of resistance to radiation. Here, we discussed the relationships between radioresistance and mitochondrial and glucose metabolic pathways, aiming to elucidate the interplay between the tumor cell metabolism and radiotherapy resistance. In this review, we additionally summarized the potential therapeutic targets in the metabolic pathways. The aim of this review was to provide a theoretical basis and relevant references, which may lead to the improvement of the sensitivity of radiotherapy and prolong the survival of cancer patients.

/pdf/role-of-metabolism-in-cancer-cell-radioresistance-and-4s49140xzk.pdf

Role of metabolism in cancer cell radioresistance and radiosensitization methods.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates the expression of genes related to cell cycle, cell survival, and immune response associated with cancer progression and malignancy in a number of cancer types. Once activated, STAT3 forms a homodimer and translocates to the nucleus where it binds DNA promoting the translation of target genes associated with antiapoptosis, angiogenesis, and invasion/migration. In normal cells, levels of activated STAT3 remain transient; however, STAT3 remains constitutively active in approximately 70% of human solid tumors. The pivotal role of STAT3 in tumor progression has promoted a campaign in drug discovery to identify small molecules that disrupt the function of STAT3. A range of approaches have been used to identify novel small molecule inhibitors of STAT3, including high-throughput screening of chemical libraries, computational-based virtual screening, and fragment-based design strategies. The most common approaches ...

Strategies and Approaches of Targeting STAT3 for Cancer Treatment.

Janus tyrosine kinase (JAK) family of proteins have been identified as crucial proteins in signal transduction initiated by a wide range of membrane receptors. Among the proteins in this family JAK2 has been associated with important downstream proteins, including signal transducers and activators of transcription (STATs), which in turn regulate the expression of a variety of proteins involved in induction or prevention of apoptosis. Therefore, the JAK/STAT signaling axis plays a major role in the proliferation and survival of different cancer cells, and may even be involved in resistance mechanisms against molecularly targeted drugs. Despite extensive research focused on the protein structure and mechanisms of activation of JAKs, and signal transduction through these proteins, their importance in cancer initiation and progression seem to be underestimated. This manuscript is an attempt to highlight the role of JAK proteins in cancer biology, the most recent developments in targeting JAKs, and the central role they play in intracellular cross-talks with other signaling cascades.

/pdf/do-we-know-jack-about-jak-a-closer-look-at-jak-stat-3tiju50mes.pdf

"Do We Know Jack" About JAK? A Closer Look at JAK/STAT Signaling Pathway.

Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus, there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment (TME), which contains diverse cell populations, signaling factors and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Antitumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells and regulatory T cells, as well as immune checkpoints like programmed death-1. Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy.

The tumor microenvironment in esophageal cancer

The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing anti-tumor immune responses. Through an unbiased approach, we have established that IL-6 mediates crosstalk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL-6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant 3D organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL-6Rα antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL-6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head-and-neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL-6 is a major contributor to the dynamic crosstalk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL-6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.

/pdf/il-6-mediates-cross-talk-between-tumor-cells-and-activated-5g6zzigmx0.pdf

IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment.

Triptolide (TPL/TL) is a natural drug with novel anticancer effects. Preclinical studies indicated that TPL inhibits cell proliferation, induces cell apoptosis, inhibits tumor metastasis and enhances the effect of other therapeutic methods in various cancer cell lines. Multiple molecules and signaling pathways, such as caspases, heat-shock proteins, NF-κB, and deoxyribonucleic acid (DNA) repair-associated factors, are associated with the anti-cancer effect. TPL also improves chemoradiosensitivity in cancer therapy. Phase I trials indicate the potential clinical value of TPL use. However, further trials with larger sample sizes are needed to confirm these results.

/pdf/targets-and-molecular-mechanisms-of-triptolide-in-cancer-53adpzfi59.pdf

Targets and molecular mechanisms of triptolide in cancer therapy.

The radiation resistance of prostate cancer remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of berberine, a commonly used natural product, on the radiosensitivity of prostate cancer. Prostate cancer cell line LNCaP and DU-145 were subjected to hypoxia and/or ionizing radiation (IR), in the presence or absence of berberine treatment. Cell growth and colony formation, and apoptosis were evaluated. Moreover, LNCaP cells were xenografted into nude mice and subjected to IR and/or berberine treatment. The expression of HIF-1α and VEGF in prostate cancer cells and xenografts was detected by Western blot analysis. Berberine increased radiosensitivity of prostate cancer cells and xenografts in a dose dependent manner, and this was correlated with the inhibition of HIF-1α and VEGF expression. Berberine may inhibit the expression of HIF-1α and VEGF and thus confer radiosensitivity on prostatic cancer cells. Berberine has potential application as an adjuvant in radiotherapy of prostatic cancer. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1519827543125021
 .

/pdf/berberine-inhibits-the-expression-of-hypoxia-induction-1nms7gno3a.pdf

Berberine inhibits the expression of hypoxia induction factor-1alpha and increases the radiosensitivity of prostate cancer

The radioresistance of esophageal squamous cell carcinoma (ESCC) remains an obstacle for the effective radiotherapy of ESCC. This study aimed to investigate the radiosensitization of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor stattic. ECA109, TE13, and KYSE150 cell lines were exposed to hypoxia and treated with stattic or radiation, alone or in combination. Cell proliferation, colony formation, apoptosis, and double-stranded DNA breaks (DSBs) were examined. In addition, ECA109 cells were xenografted into nude mice and treated with radiation and/or stattic. The levels of STAT3, p-STAT3, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in ESCC cells and xenografts were detected by Western blot and immunohistochemical analysis. Our results showed that stattic efficiently radiosensitized ESCC cells and xenografts, especially under hypoxia. Moreover, stattic inhibited STAT3 activation and downregulated HIF-1α and VEGF expression. In conclusion, stattic confers radiosensitivity in ESCC cells in vitro and in vivo and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting.

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma

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Targets and molecular mechanisms of triptolide in cancer therapy.

Berberine inhibits the expression of hypoxia induction factor-1alpha and increases the radiosensitivity of prostate cancer

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma