Increased MCL-1 synthesis promotes irradiation-induced nasopharyngeal carcinoma radioresistance via regulation of the ROS/AKT loop

Abstract

Worldwide, nasopharyngeal carcinoma (NPC) is a rare head and neck cancer; however, it is a common malignancy in southern China. Radiotherapy is the most important treatment strategy for NPC. However, although radiotherapy is a strong tool to kill cancer cells, paradoxically it also promotes aggressive phenotypes. Therefore, we mimicked the treatment process in NPC cells in vitro. Upon exposure to radiation, a subpopulation of NPC cells gradually developed resistance to radiation and displayed cancer stem-cell characteristics. Radiation-induced stemness largely depends on the accumulation of the antiapoptotic myeloid cell leukemia 1 (MCL-1) protein. Upregulated MCL-1 levels were caused by increased stability and more importantly, enhanced protein synthesis. We showed that repeated ionizing radiation resulted in persistently enhanced reactive oxygen species (ROS) production at a higher basal level, further promoting protein kinase B (AKT) signaling activation. Intracellular ROS and AKT activation form a positive feedback loop in the process of MCL-1 protein synthesis, which in turn induces stemness and radioresistance. AKT/MCL-1 axis inhibition attenuated radiation-induced resistance, providing a potential target to reverse radiation therapy-induced radioresistance.

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

“…The mRNA and protein expression of MCL-1 was found to be elevated in chemoresistant OSCC cells, and inhibition of MCL-1 using genetic or pharmacological methods induced cell death in OSCC cells resistant to either cisplatin, fluorouracil or docetaxel [ 42 ]. Radiation-induced stemness and radioresistance in nasopharyngeal carcinoma (NPC) largely depended on the upregulation of MCL-1 protein, which was attributed to intracellular reactive oxygen species and Akt activation following repeated ionizing radiation [ 43 ]. MCL-1 expression was also associated with deubiquitinase USP9X-mediated radioresistance in hematological tumors [ 44 ].…”

Targeting Mcl-1 Degradation by Bergenin Inhibits Tumorigenesis of Colorectal Cancer Cells

“…Bergenin ( Figure 1 A), a natural product, has experimentally exhibited multiple pharmacological activities [ 16 ]. To determine the antitumor effects of bergenin on human CRC, the HCT116, HT29, and SW620 cells were treated with this compound.…”

The Role of Reprogrammed Glucose Metabolism in Cancer

“…The overexpression of induced myeloid leukemia cell differentiation protein (Mcl-1), a member of anti-apoptotic Bcl-2 family proteins, is seen in a range of human cancers [ 127 , 128 ]. The association of Mcl-1 in chemo and radiotherapy resistance in cancer cells is well-described [ 129 ]. The function of Mcl-1 is closely linked with the resistance to ABT-737, a Bcl-2 family inhibitor [ 130 ].…”