ALDHHIGH Population Is Regulated by the AKT/β-Catenin Pathway in a Cervical Cancer Model

Abstract

ALDH is an enzyme involved in different cellular processes, including cancer. It has been shown that a cellular subpopulation with high ALDH activity (ALDH HIGH) within a tumor is related to functional capabilities such as stemness, chemoresistance, and tumorigenicity. However, few studies have focused on determining the mechanisms behind ALDH activity within the cells. Previously, our group reported that ALDH HIGH cells have higher tumorigenicity in Cervical Cancer (CC) cell lines. Based on this, we were interested to know the molecular mediators of the ALDH HIGH cells, specifically β-catenin, inasmuch as β-catenin is regulated through different pathways, such as Wnt signaling, and that it acts as a transcriptional co-activator involved in cancer progression. In this work, we show that the increase in ALDH HIGH cell percentage is reverted by β-catenin knockdown. Consistently, upon GSK3-β inactivation, a negative regulator of β-catenin, we observed an increase in ALDH HIGH cells. Additionally, we observed a low percentage of cells positive for Fzd receptor, suggesting that in our model there is a low capacity to respond to Wnt ligands. The analysis of ALDH HIGH cells in a sphere formation model demonstrated the active state of AKT. In accordance with this, impairment of AKT activity not only reduced β-catenin active state, but also the percentage of ALDH HIGH cells. This corroborates that AKT acts upstream of β-catenin, thus affecting the percentage of ALDH HIGH cells. In conclusion, our results show that ALDH HIGH cells are dependent on β-catenin, in spite of the Wnt pathway seems to be dispensable, while AKT emerges as central player supporting a mechanism in this important axis that is not yet well known but its analysis improves our understanding of ALDH activity on CC.

Aldehyde dehydrogenase 1A1 and 1A3 isoforms – mechanism of activation and regulation in cancer

“…Following study of ALDH+ cervical cancer cells revealed that ALDH expression could be triggered by β-catenin through a Wnt/Frizzled-independent mechanism, and this effect is downstream of AKT activity. Pharmacological inhibition of AKT reduced the active form of the β-catenin and inactive form of GSK3 in ALDH+ cells and reduced ALDH protein level and activity [42] . Mucin 1.…”

“…Analysis of the ALDH1A1 promoter region displayed two main β-catenin/TCF binding sites 5′-A/T A/T CAAAG-3′ [41] . β-catenin can be triggered also by Wnt independent mechanism, downstream of AKT activity [42] .

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New Aspects in the Mechanism of Action of ALDH1A1 and 1A3 Isoforms in Carcinogenesis

“…Briefly, ALDH1A1 is activated by the Wnt pathway via β-catenin and T-cell factor in breast cancer and prostate cancer [2]. β-catenin can be activated also by a Wnt-independent mechanism, downstream of the Akt axis, as reported in ALDH high cervical cancer cells [3]. Transforming growth factor β (TGF-β) pathway results in a downregulation of ALDH1A1 through Smad4 in cholecarcinoma [4], breast cancer [5], pancreatic cancer [6], and uterine endometrioid cancer [7].…”

A novel prognostic signature based on cancer stemness and metabolism-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

“…It serves as a prognostic factor for recurrence following surgical intervention in CESC [16]. ALDH1B1 gene expression exhibited a positive association in CESC [17]. PLOD2 is an effective prognostic marker, which is related to the immune infiltration of cervical cancer [18].…”