Monocarboxylate transporter 1 is a novel target for breast cancer stem like‐cell inhibition by diallyl trisulfide

Abstract

Diallyl trisulfide (DATS) is a promising small molecule phytochemical that exhibits in vitro and in vivo activity in multiple preclinical solid tumor models including breast cancer, but the underlying mechanism is not fully understood.We have shown previously that forkhead box Q1 (FoxQ1) transcription factor is a novel target for breast cancer stem-like cells (bCSC) inhibition by DATS.Analysis of the breast TCGA (The Cancer Genome Atlas) data revealed that FoxQ1 expression was positively associated with that of SLC16A1/monocarboxylate transporter 1 (MCT1). Western blot analysis confirmed increased expression of MCT1 protein in SUM159 (basal-like) and MCF-7 cells (luminal-type) stably transfected to overexpress FoxQ1. Furthermore, FoxQ1 was recruited to the promoter of SLC16A1/MCT1. Treatment of SUM159 and MCF-7 cell lines with DATS resulted in suppression of MCT1 protein level that was accompanied by a decrease in intracellular and secreted levels of lactate. Overexpression or knockdown of MCT1 protein failed to alter DATS-mediated inhibition of colony formation or cell migration when compared to corresponding control cells. On the other hand, overexpression of MCT1 protein conferred partial but statistically significant protection against DATS-mediated inhibition of bCSC fraction (CD49f high /CD44 high and aldehyde dehydrogenase 1 activity). The size of the mammospheres was relatively smaller in the DATS-treated group compared to control group. Inhibition of bCSC upon DATS treatment was augmented by knockdown of the MCT1 protein. In conclusion, the present study reveals that MCT1 is a novel target for bCSC inhibition by DATS treatment.

Diallyl Trisulfide Induces ROS-Mediated Mitotic Arrest and Apoptosis and Inhibits HNSCC Tumor Growth and Cancer Stemness

“…Studies have shown that phytochemicals like benzyl isothiocyanate [45][46][47], sulforaphane [48], and withaferin A [49] suppressed the growth of CSC, along with bulk cancer cells. Recently, Kim et al reported that DATS treatment decreased CSC fraction in breast cancer, both in vitro and in vivo [26,36], and on this basis we anticipated the effects of DATS on HNSCC stem cells. DATS treatment significantly lowered the CD133 high /CD44 high fraction, ALDH1 activity and spheroid formation, and the inhibition of CSC was evident at non-cytotoxic doses of DATS.…”

“…Epidemiological studies and population-based case-control studies revealed the health benefits of Allium vegetables, whose therapeutic benefits are attributed to organosulfur compounds (OSCs), diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) [33]. DATS is the most effective OSC found in garlic and has been shown to conduct anticancer activities against prostate cancer [34,35], breast cancer [25,36], and lung cancer [37,38]. The present study established its anticancer activity against HNSCC.…”

The Anticancer Effects of the Garlic Organosulfide Diallyl Trisulfide through the Attenuation of B[a]P-Induced Oxidative Stress, AhR Expression, and DNA Damage in Human Premalignant Breast Epithelial (MCF-10AT1) Cells

“…This effect is enhanced when these transfected cells are treated with B[a]P, most likely due to the impact of DATS on the B[a] P-induced mutations generated during the chemical-induced transformation of these cells. DATS's inhibitory effects on in vivo and in vitro cancer models are much more pronounced than in in vitro chemical-induced epithelial cell models [41,[48][49][50][51][52]. When DATS was used in this study, it was an effective attenuator of B[a]P-induced proliferation and clonogenic formation in these premalignant cells.…”

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer

“…To maintain glycolysis efficiency and avoid cell death, the continuously produced and accumulated lactate need to be rapidly transported into the tumor microenvironment (TME). Previous studies reported that suppression of SLC16A1 was accompanied by a decrease in secreted levels of lactate and ATP production, increased intracellular lactate levels, inhibited cancer growth and metastasis, as well as induce apoptotic cell death [46][47][48], suggesting that blocking SLC16A1mediated glycolysis might contribute to improvement of cancer treatment. In addition, RAB11A, the first identified member of small GTPase family, was overexpressed in various cancer tissues and associated with the clinical outcomes of cancer patients [49,50].…”