Cell Signaling Pathways That Promote Radioresistance of Cancer Cells

Abstract

Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells.

Keywords: DNA repair; apoptosis; autophagy; cell cycle checkpoint; cell signaling pathways; radiation therapy.

Figure 1

Cellular response to radiation-induced DNA damage. Ionizing radiation (IR) induces DNA damage in cancer cells in the form of either single-strand breaks (SSB) or double-strand breaks (DSB). DNA damage sensed by cells results in various cellular responses: senescence, apoptosis, autophagy, cell cycle arrest, and DNA repair. Signaling pathways that promote cell cycle checkpoint activation/DNA repair and inhibition of apoptosis can protect cancer cells from IR-induced cytotoxicity, promoting survival and the subsequent radiation resistance of cancer cells.

Figure 2

Core factors in DNA damage response and DNA repair networks. Ionizing radiation causes DNA damage that activates ATM, ATR, and DNA-PK kinases, which transmit signals to their downstream targets to promote DNA repair by NHEJ and HR while activating checkpoint response pathways to arrest the cell cycle. If the DNA damage cannot be repaired, other cellular signaling responses, such as those that lead to apoptosis, autophagy, and senescence induction will be triggered.

Figure 3

Radiation induces activation of HER receptors, which, in turn, leads to the activation of PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways that promote cell survival.

Figure 4

PI3K/AKT mediated signaling promotes cell survival. (i) Activation of PI3K by radiation leads to the phosphorylation/activation of AKT; (ii) AKT phosphorylates and inhibits the pro-apoptotic proteins Bad, Bax, and Bim; (iii) AKT activates Nuclear factor (NF)-κB transcription factor, resulting in the up-regulation of the expression of pro-survival genes Bcl-2 and Bcl-xL; (iv) AKT phosphorylates the pro-survival protein XIAP, which binds to and inhibits caspase3/7/9 that are required for apoptosis induction; (v) AKT phosphorylates/activates the mammalian target of rapamycin (mTOR) kinase, which then phosphorylates and activates the anti-apoptotic protein Mcl-1; (vi) phosphorylation of Forkhead box O (FOXO)3a (transcription factor) by AKT results in the inhibition and nuclei exclusion of FOXO3a, which otherwise up-regulates the gene expression of pro-apoptotic proteins Bim and Noxa.

Figure 5

Overview of the NF-κB signaling pathway. NF-κB is inhibited by IκB in the cytoplasm. Upon activation by upstream signals (e.g., Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-1, Chemo, IR), IκK (IκB kinase) phosphorylates IκB, resulting in its proteasomal degradation by the Skp_Cullin_F-box (SCF)^βTRCP–ubiquitin ligase complex. Consequently, this frees NF-κB, allowing it to be translocated into the nucleus to activate gene transcriptions that promote proliferation and survival.

Figure 6

Overview of the hypoxia-inducible factor 1 (HIF-1) signaling pathway under normoxia and hypoxia conditions. Under normoxia, HIF-1α is hydroxylated by prolyl-4-hydroxylase, leading to its interaction with von Hippel-Lindau (VHL) and subsequent proteasomal degradation. Under hypoxia, HIF-1α accumulates and translocates to the nucleus and forms a complex with HIF-1β. The heterodimer complexes then bind to the hypoxia response element (HRE) with p300/CBP and activate the expression of their targeted genes, which include those that promote angiogenesis (e.g., VEGF), autophagy (e.g., LC3-II), anti-apoptosis (e.g., BCL-2), cancer stem cell stemness (e.g., Snail), and energy metabolism reprogramming e.g., GLUT1).

Figure 7

Yes-associated protein 1 (YAP) transcriptional activity promotes radiation-therapy resistance. As a master transcriptional coactivator of TEA Domain Transcription Factor (TEAD), YAP activates the transcription of many essential genes that support survival, DNA repair, proliferation, and epithelial-mesenchymal transition (all of which can synergistically drive cancer cells resilient to radiation-induced cytotoxicity and developing radioresistance.

Figure 8

Overview of ionizing radiation-induced signaling pathways that promote tumor cell survival and radiation resistance. Activation of ATM, ATR, and DNA-PK signalings by radiation leads to cell cycle arrest and DNA repair. Activation of HER, ERK1/2, and AKT signaling pathways by radiation inhibits apoptosis induction and promotes cell cycle checkpoint response and DNA repair. Antioxidants produced by glycolysis reduce ROS levels in tumor cells to sustain HIF-1α activity that promotes radioprotective mechanisms.