Nanog Signaling Mediates Radioresistance in ALDH-Positive Breast Cancer Cells.

Mozhgan Dehghan Harati,H Peter Rodemann,Mahmoud Toulany

doi:10.3390/ijms20051151

Mozhgan Dehghan Harati, H Peter Rodemann + Show 1 more

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https://doi.org/10.3390/ijms20051151

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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.

Highlights

Breast cancer is the most commonly diagnosed cancer in women worldwide
To determine whether aldehyde dehydrogenase (ALDH)-positive breast cancer cells are more radioresistant than ALDH-negative breast cancer cells, both cell populations were isolated from HBL-100 and SKBR3 via fluorescence-activated cell sorting (FACS) based on an Aldefluor assay, see Figure 1A
High aldehyde dehydrogenase1 (ALDH1) activity is well recognized to serve as a cancer stem cells (CSCs) marker in different tumor types [9,27,28,29]

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer in women worldwide. Despite an improvement in the survival rate of patients, breast cancer is still the major cause of death in women aged 20–59 years [1,2]. Tumor relapse and metastasis are the prime factors underlying cancer patient death [3]. Several reports have indicated that tumors consist of a heterogenous cell population that includes bulk tumor cells and tumor-initiating/cancer stem cells (CSCs) [4]. CSCs are capable of tumor initiation and self-renewal and can give rise to bulk populations of nontumorigenic cancer cells through differentiation [5]. CSCs have been suggested as one of the underlying reasons for tumor recurrence and therapy resistance [3]

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