No abstract

A fundamental component of cellular radioresponse is the translational control of gene expression. As a critical regulator of translational control is the eIF4F cap binding complex, we investigated whether eIF4A, the RNA helicase component of eIF4F, can serve as a target for radiosensitization. Knockdown of eIF4A using siRNA reduced translational efficiency, as determined from polysome profiles, and enhanced tumor cell radiosensitivity as determined by clonogenic survival. The increased radiosensitivity was accompanied by a delayed dispersion of radiation-induced γH2AX foci, suggestive of an inhibition of DNA double strand break repair. Studies were then extended to (-)-SDS-1-021, a pharmacological inhibitor of eIF4A. Treatment of cells with the rocaglate (-)-SDS-1-021 resulted in a decrease in translational efficiency as well as protein synthesis. (-)-SDS-1-021 treatment also enhanced the radiosensitivity of tumor cell lines. This (-)-SDS-1-021-induced radiosensitization was accompanied by a delay in radiation-induced γH2AX foci dispersal, consistent with a causative role for the inhibition of double strand break repair. In contrast, while (-)-SDS-1-021 inhibited translation and protein synthesis in a normal fibroblast cell line, it had no effect on radiosensitivity of normal cells. Subcutaneous xenografts were then used to evaluate the in vivo response to (-)-SDS-1-021 and radiation. Treatment of mice bearing subcutaneous xenografts with (-)-SDS-1-021 decreased tumor translational efficiency as determined by polysome profiles. While (-)-SDS-1-021 treatment alone had no effect on tumor growth, it significantly enhanced the radiation-induced growth delay. These results suggest that eIF4A is a tumor selective target for radiosensitization.

Increased ribosome biogenesis is a distinguishing feature of cancer cells, and small molecule inhibitors of ribosome biogenesis are currently in clinical trials as single agent therapy. It has been previously shown that inhibiting ribosome biogenesis through the inhibition of nuclear export of ribosomal subunits sensitizes tumor cells to radiotherapy. In this study, the radiosensitizing potential of CX-5461, a small molecule inhibitor of RNA polymerase I, was tested. Radiosensitization was measured by clonogenic survival assay in a panel of four tumor cell lines derived from three different tumor types commonly treated with radiation. 50 nM CX-5461 radiosensitized PANC-1, U251, HeLa, and PSN1 cells with dose enhancement factors in the range of 1.2–1.3. However, 50 nM CX-5461 was not sufficient to inhibit 45S transcription alone or in combination with radiation. The mechanism of cell death with the combination of CX-5461 and radiation occurred through mitotic catastrophe and not apoptosis. CX-5461 inhibited the repair and/or enhanced the initial levels of radiation-induced DNA double strand breaks. Understanding the mechanism of CX-5461-induced radiosensitization should be of value in the potential application of the CX-5461/radiotherapy combination in cancer treatment.

Pornography addiction is an area of increasing concern, particularly due to the ubiquitous nature of pornographic material on the Internet. Even so, there is no formal Diagnostic and Statistical Manual of Mental Disorders (DSM-5) inclusion of compulsive pornography use as a behavioral addiction. Although the psychosocial impacts of pornography addiction have been studied, the risk of direct skin injuries and behavioral changes brought about by excessive pornography usage remain to be seen. Adult males constitute the majority of cases of engaging in risky and violent sexual behaviors with an unclear association with pornography consumption. Adult females may be likely to copy pubic hair trimming patterns analogous to those seen in pornographic content, even though attitudes towards labiaplasty are unclear. Finally, adolescents regularly exposed to pornography have been found to replicate sexual activity seen in pornographic material and have earlier sexual activity. In the literature evaluated, an association between pornographic material and direct cutaneous disease remains a major area of further research.

Supplementary Figure from Inhibition of the Translation Initiation Factor eIF4A Enhances Tumor Cell Radiosensitivity