Nanog Signaling Mediates Radioresistance in ALDH-Positive Breast Cancer Cells

Abstract

Recently, cancer stem cells (CSCs) have been identified as the major cause of both chemotherapy and radiotherapy resistance. Evidence from experimental studies applying both in vitro and in vivo preclinical models suggests that CSCs survive after conventional therapy protocols. Several mechanisms are proposed to be involved in CSC resistance to radiotherapy. Among them, stimulated DNA double-strand break (DSB) repair capacity in association with aldehyde dehydrogenase (ALDH) activity seems to be the most prominent mechanism. However, thus far, the pathway through which ALDH activity stimulates DSB repair is not known. Therefore, in the present study, we investigated the underlying signaling pathway by which ALDH activity stimulates DSB repair and can lead to radioresistance of breast cancer cell lines in vitro. When compared with ALDH-negative cells, ALDH-positive cells presented significantly enhanced cell survival after radiation exposure. This enhanced cell survival was associated with stimulated Nanog, BMI1 and Notch1 protein expression, as well as stimulated Akt activity. By applying overexpression and knockdown approaches, we clearly demonstrated that Nanog expression is associated with enhanced ALDH activity and cellular radioresistance, as well as stimulated DSB repair. Akt and Notch1 targeting abrogated the Nanog-mediated radioresistance and stimulated ALDH activity. Overall, we demonstrate that Nanog signaling induces tumor cell radioresistance and stimulates ALDH activity, most likely through activation of the Notch1 and Akt pathways.

Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents

“…58 Furthermore, the status of Nanog determines the switch between cancer cells and CSCs. 67 Moreover, Nanog expression was associated with enhanced ALDH activity and cellular radioresistance 68 and chemoreistance. 69 Sox2.…”

“…213 Nanog regulated Notch signaling along with ALDH activity and radiotherapy resistance in breast cancer. 68 Moreover, crosstalk between Notch and NF-κB contributed to therapy resistance in triple-negative breast cancer (TNBC): 215 Jagged1 triggers nuclear, NF-κB-dependent transcription of antiapoptotic gene cIAP-2. Furthermore, extracellular signals can regulate Notch.…”

Aldehyde Dehydrogenase, a Therapeutic Target in Chordoma: Analysis in 3D Cellular Models

“…Cancer stem cells have increased activity of ALDH1 and ALDH3, and this is particularly used to isolate them from tumor bulk. They are involved in resistance to both chemo- and radiotherapy in most solid tumors [ 16 , 17 , 18 , 21 , 46 ]. In chordoma, the ALDH activity has been measured in cell lines.…”

“…A high ALDH activity has already been correlated with resistance to treatment in multiple solid tumors. For instance, ALDH-positive breast cancer cells are radioresistant in vitro [ 16 , 17 ]. ALDH1-positive cells exhibit a radioresistant phenotype enhanced with hypoxia in cervical cancer [ 18 ].…”

Role of miRNA manipulation on methylation states of breast cancer stem cell-related gene: Methylation status and miRNAs on BCSCs

“…It is also overexpressed in different types of cancer including BC. Also, NANOG forms the core of the transcription network with SOX2 21 .…”