Radiation Resistance: A Matter of Transcription Factors

Abstract

Currently, radiation therapy is one of the standard therapies for cancer treatment. Since the first applications, the field of radiotherapy has constantly improved, both in imaging technologies and from a dose-painting point of view. Despite this, the mechanisms of resistance are still a great problem to overcome. Therefore, a more detailed understanding of these molecular mechanisms will allow researchers to develop new therapeutic strategies to eradicate cancer effectively. This review focuses on different transcription factors activated in response to radiotherapy and, unfortunately, involved in cancer cells' survival. In particular, ionizing radiations trigger the activation of the immune modulators STAT3 and NF-κB, which contribute to the development of radiation resistance through the up-regulation of anti-apoptotic genes, the promotion of proliferation, the alteration of the cell cycle, and the induction of genes responsible for the Epithelial to Mesenchymal Transition (EMT). Moreover, the ROS-dependent damaging effects of radiation therapy are hampered by the induction of antioxidant enzymes by NF-κB, NRF2, and HIF-1. This protective process results in a reduced effectiveness of the treatment, whose mechanism of action relies mainly on the generation of free oxygen radicals. Furthermore, the previously mentioned transcription factors are also involved in the maintenance of stemness in Cancer Stem Cells (CSCs), a subset of tumor cells that are intrinsically resistant to anti-cancer therapies. Therefore, combining standard treatments with new therapeutic strategies targeted against these transcription factors may be a promising opportunity to avoid resistance and thus tumor relapse.

Keywords: ROS - reactive oxygen species; cancer stem cells; inflammation; radiation resistance; radiotherapy; transcription factors.

Figure 1

Mechanisms of STAT3 activation in response to IR. Depending on the tumor type, STAT3 can be activated in different ways after IR exposure. (A) STAT3 phosphorylation through the activation of HER2 receptor in HER2-positive breast cancer; (B) role of IL-6 signaling in the activation of the JAK2/STAT3 pathway in pharyngeal cancer, HCC and prostate cancer; (C) involvement of MUC1 in HCC radioresistance; (D) formation of PAG1-Integrin β1 complexes to induce the activation of STAT3 in laryngeal cancer.

Figure 2

Summary of the main pathways activated by STAT3 following radiation treatment. FOXM1 is known to be able to regulate its own expression (91) and STAT3 transcription (92) establishing a positive feedback loop. Moreover, it induces Survivin expression, which can exert both Caspase-dependent and -independent downstream effects. Finally, STAT3 mediates the activation of genes involved in the maintenance of the CSCs pool, providing another system to promote radioresistance.

Figure 3

Schematic representation of the radiation-induced NF-κB signaling network. The activation of NF-κB is mediated by different stimuli: (A) the EGFR signaling pathway, especially through the activity of HER2; (B) the radiation-induced cytokines; and (C) DSBs generated by IR-induced ROS. The transcriptional program of NF-κB leads to several downstream events, which result in enhanced aggressiveness, increased survival and better fitness of cancer cells.

Figure 4

Activators and effectors of NRF2 signaling pathway following IR exposure. (A, B) KEAP1-dependent activation of NRF2: IL-6 induces an increase in the phosphorylated form of p62, which combines with the NRF2 inhibitor KEAP1, leading to the release and translocation of NRF2 into the nucleus (A); (B) evidence of mTORC1 involvement in p62 phosphorylation. (C) A putative KEAP1-independent mechanism of NRF2 activation. (D) Canonical transcriptional targets of NRF2; (E) NRF2-mediated regulation of NOTCH1 signaling.

Figure 5

Summary of the pathways involved in the HIF-1 transcriptional activation after IR and its downstream effectors. Several clues can lead to HIF-1 activation. The most known is the presence of (A) a hypoxic environment, a condition frequently found in most solid tumors. Also, (B) ionizing radiations induce the activity of this hypoxia-related TF by the induction of ROS. Together with these external stimuli, congenital or acquired mutations promote HIF-1 activity, such as the ones found in its negative regulators: (C) PHDs and VHL. (D) Moreover, RTK receptors, like HER2, are found to induce HIF-1, which is particularly true for certain types of tumors, like breast cancers. (E) Lastly, HIF-1 can be activated also by the aberrant function of its deubiquitinase, UCHL1. The network established by HIF-1 transcriptional activity confers cancer cells more aggressive characteristics and protects them from the harmful effects of radiation therapy.