Dual effects of active ERK in cancer: A potential target for enhancing radiosensitivity (Review)

Abstract

Ionizing radiation (IR) is an important cancer treatment approach. However, radioresistance eventually occurs, resulting in poor outcomes in patients with cancer. Radioresistance is associated with multiple signaling pathways, particularly pro-survival signaling pathways. The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is an important signaling pathway that initiates several cellular processes and is regulated by various stimuli, including IR. Although numerous studies have demonstrated the pro-survival effects of active ERK, activation of ERK has also been associated with cell death, indicating that radiosensitization may occur by ERK stimulation. In this context, the present review describes the associations between ERK signaling, cancer and IR, and discusses the association between ERK and its pro-survival function in cancer cells, including stimuli, molecular mechanisms, clinical use of inhibitors and underlying limitations. Additionally, the present review introduces the view that active ERK may induce cell death, and describes the potential factors associated with this process. This review describes the various outcomes induced by active ERK to prompt future studies to aim to enhance radiosensitivity in the treatment of cancer.

MMP-9 Reinforces Radiation-Induced Delayed Invasion and Metastasis of Surviving Neuroblastoma Cells Through Second-Signaling Positive Feedback With NFkB Via Both ERK and IKK Activation

“…First, our results recognized the reversal of RT-induced ERK phosphorylation when we selectively blocked the RT-induced MMP9. We and others have shown that RT induces ERK phosphorylation in surviving tumor cells (Aravindan et al 2013c;Ala et al 2020;Lu et al 2020). Likewise, regulation of ERK phosphorylation by MMP9 in the presence and/or absence of RT has been previously documented (Bhoopathi et al 2008;Kunigal et al 2008;Gogineni et al 2009).…”

Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

“…Activation of this chemokine signaling pathway leads to activation of the pERK pathway, that plays a significant role in regulating cancer progression. It is important to note that ERK activation can play dual roles in cancer in a context-dependent manner by either activating pro-survival or apoptotic mechanisms [40]. Clinical studies also indicate a variable association between ERK activation and tumor progression and could correlate with either an oncogenic or a tumor-suppressing role [41].…”

Circular RNAs: Emerging Regulators of the Major Signaling Pathways Involved in Cancer Progression

“…Deregulated MAPK signaling is implicated in the progression of a wide range of cancers and occurs via multiple mechanisms, including abnormal expression of RTKs and/or genetic mutations that trigger the activation of RTKs and, thus, of downstream signaling molecules in the absence of appropriate stimuli [ 71 ]. Numerous studies focus on the dual role of MAPK signaling pathways that can mediate cell transformation, as well as apoptosis, such as the ERK and JNK signaling pathways [ 72 , 73 , 74 ]. However, there is still much to be deciphered in terms of regulation and mode of action in both preclinical and clinical research.…”