Housekeeping genes (HKGs) are essential for basic maintenance of a variety of cellular processes. They ideally maintain uniform expression independent of experimental conditions. However, the effects of ionizing radiation (IR) on HKG expression is unclear. Statistical algorithms, geNorm and Normfinder were used for estimating the stability of HKGs as raw quantification cycle (Cq) values were not a reliable factor for normalization. Head and neck, non-small lung and pancreas cells were exposed to 2, 4 and 6 Gy IR doses and expression of fourteen HKGs was measured at 5 min to 48 h post-irradiation within a given tissue. Paired and single cell line analyses under these experimental conditions identified TATA-Box Binding Protein (TBP) and Importin 8 (IPO8) to be stable in non-small cell lung cancer. In addition to these two genes, Ubiquitin C (UBC) in head and neck cancer and Transferrin receptor (TFRC) and β-Glucuronidase (GUSB) in pancreatic cancer were identified to be stable as well. In summary we present a resource for top ranked five stable HKGs and their transcriptional behavior in commonly used cancer model cell lines and suggest the use of multiple HKGs under radiation treatment conditions is a reliable metric for quantifying gene expression.
Antitumor alkyl phospholipid (APL) analogs comprise a group of structurally related molecules with remarkable tumor selectivity. Some of these compounds have shown radiosensitizing capabilities. CLR127 is a novel, clinical-grade antitumor APL ether analog, a subtype of synthetic APL broadly targeting cancer cells with limited uptake in normal tissues. The purpose of this study was to investigate the effect of CLR127 to modulate radiation response across several adult and pediatric cancer types as well as in murine xenograft models of human prostate adenocarcinoma, neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma., CLR127 demonstrated selective uptake in cancer cells compared to normal cells. In cancer cells, CLR127 treatment prior to radiation significantly decreased clonogenic survival , and led to increased radiation-induced double-stranded DNA (dsDNA) breakage compared with radiation alone, which was not observed in normal controls. In animal models, CLR127 effectively increased the antitumor response to fractionated radiotherapy and led to delayed tumor regrowth at potentially clinically achievable doses. In conclusion, our study highlights the ability of CLR127 to increase radiation response in several cancer types. Given almost universal uptake of CLR127 in malignant cells, future research should test whether the observed effects can be extended to other tumor types. Our data provide a strong rationale for clinical testing of CLR127 as a tumor-targeted radiosensitizing agent..
Gli1 expressing neural stem cells, in the subventricular zone of the adult mammalian brain, respond to demyelination injury by differentiating into oligodendrocytes. We have identified Gpnmb as a novel regulator of oligodendrogenesis in Gli1 neural stem cells, whose expression is induced by TGFβ1 signaling via Gli1, in response to a demyelinating injury. Upregulation of Gpnmb further activates the TGFβ1 pathway by increasing the expression of the TGFβ1 binding receptor subunit, TGFβR2. Thus the TGFβ1→Gli1→Gpnmb→TGFβR2 signaling pathway forms a feed forward loop for sustained activation of TGFβ1 signaling in Gli1 neural stem cells, resulting in inhibition of their differentiation into mature oligodendrocytes following demyelination.
The cancer genome atlas (TCGA) has identified androgen receptor (AR) to be mutated, deleted and amplified across human lung squamous cell carcinoma and adenocarcinoma. Expression of AR is critical for early lung development. However, the intriguing expression of AR in non-small cell lung cancer (NSCLC) opens up an alternative treatment paradigm in the event of onset of clinical resistance to lung cancer drugs. To investigate this potential, a) 10 NSCLC cell lines and 3 control prostate cancer cell lines were stimulated with synthetic AR agonist, R1881 at 24, 48 and 72 hours. 0.5-4-fold RNA and protein expression was found across these lung cancer cell lines when compared to unstimulated cells. b) droplet digital PCR revealed varying copies of AR DNA when benchmarked to prostate AR. c) cell proliferation assays of these cell lines with enzalutamide (MVD3100) treatment resulted in 50-65% cell survival at concentrations ranging from 10 - 25 µM. d) Immunohistochemical staining of AR in a NSCLC human tissue microarray (TMA) revealed 10 out of 88 patients (11%) to have AR positive staining in their tumor. This included 6 adenocarcinomas and 2 squamous cell carcinomas. 8 patients had focal while 2 had diffuse staining. Validation of the TMA performed with whole mount slides confirmed diffuse staining in these 11 samples. Taken together, these findings suggest AR is a potential therapeutic target in NSCLC and further work is underway to test these observations in drug resistant lung cancer cell lines and pre-clinical mouse models. Citation Format: Sean Brennan, Albert R. Wang, Hope Beyer, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor as a potential target in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4121. doi:10.1158/1538-7445.AM2017-4121
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