Diallyl Disulfide Inhibits Breast Cancer Stem Cell Progression and Glucose Metabolism by Targeting CD44/PKM2/AMPK Signaling.

It has been reported that diallyl disulfide (DADS) has anti-proliferative activity in many cancers. The purpose of this study was to investigate the functions of DADS and the underlying mechanisms of its effect in breast cancer stem cells (BCSCs). Mammosphere formation assay, glucose consumption assay, lactate production assay and mouse xenograft experiments were performed to explore the functions of DADS in BCSCs. ATPase activity assay, western blotting and immunohistochemistry (IHC) assay were conduct to explore the mechanisms underlying the effects of DADS in BCSCs. The results showed that DADS suppressed cell stemness and glucose metabolism in BCSCs. In vivo mouse xenograft experiments showed that DADS inhibited the proliferation and metastasis of BCSCs. Then, we continued to explore the mechanisms underlying the effects of DADS in BCSCs and found that DADS acts by targeting CD44, Pyruvate kinase M2 (PKM2) and AMP-activated protein kinase (AMPK) signaling pathways. IHC analysis of 125 breast cancer patients' tissues demonstrated that CD44, PKM2 and AMPK expression levels were positively correlated. In addition, positive CD44, PKM2 and AMPK expression was associated with poor patient overall survival (OS) and disease-free survival (DFS). In summary, DADS suppresses cell stemness, proliferation, metastasis and glucose metabolism in BCSCs partly through the inhibition of CD44/PKM2/AMPK. DADS may be used as a potential therapy for breast cancer treatment.

Xie X ，Huang X ，Tang H ，Ye F ，Yang L ，Guo X ，Tian Z ，Xie X ，Peng C ，Xie X ... -  《-》

Induction of Apoptosis in Human Leukemic Cell Lines by Diallyl Disulfide via Modulation of EGFR/ERK/PKM2 Signaling Pathways.

Luo N ，Zhao LC ，Shi QQ ，Feng ZQ ，Chen DL ，Li J ... -  《-》

Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines.

Nakagawa H ，Tsuta K ，Kiuchi K ，Senzaki H ，Tanaka K ，Hioki K ，Tsubura A ... -  《CARCINOGENESIS》

Diallyl disulfide inhibits growth and metastatic potential of human triple-negative breast cancer cells through inactivation of the β-catenin signaling pathway.

Although diallyl disulfide (DADS), an important garlic (Allium sativum) derivative, has exhibited potential anticancer activity, the molecular mechanism of this activity remains unknown. In this study, we evaluated the antitumor activity of DADS in triple-negative breast cancer (TNBC) cell lines based in vitro and in vivo models. We found that treatment with DADS resulted in decreased viability, increased apoptosis, and suppression of metastatic potential in TNBC cells. Furthermore, DADS induced dysregulation of B-cell lymphoma (Bcl)-2 family members, downregulation of matrix metalloproteinase (MMP)-9 and reversal of the epithelial-mesenchymal transition (EMT). Interestingly, DADS significantly inhibited activation of the β-catenin signaling pathway, which regulated Bcl-2 family members, MMP-9 and EMT in TNBC cells. Consistent with these in vitro findings, we also verified the anticancer potential of DADS in MDA-MB-231 xenograft mice. Treatment with DADS significantly reduced tumor volume and weight and increased apoptosis in these mice, while the expression of active β-catenin was decreased, and the downstream molecules were dysregulated. Our results show that the antitumor effect of DADS on TNBC cells is mediated by the β-catenin pathway, suggesting that DADS could be used as a potential therapeutic agent for treating or preventing breast cancer.

Huang J ，Yang B ，Xiang T ，Peng W ，Qiu Z ，Wan J ，Zhang L ，Li H ，Li H ，Ren G ... -  《-》

Apoptin Inhibits Glycolysis and Regulates Autophagy by Targeting Pyruvate Kinase M2 (PKM2) in Lung Cancer A549 Cells.

Pyruvate kinase M2 (PKM2) is a key enzyme in aerobic glycolysis and plays an important role in tumor energy metabolism and tumor growth. Ad-apoptin, a recombinant oncolytic adenovirus, can stably express apoptin in tumor cells and selectively causes cell death in tumor cells. The relationship between the anti-tumor function of apoptin, including apoptosis and autophagy activation, and the energy metabolism of tumor cells has not been clarified. In this study, we used the A549 lung cancer cell line to analyze the mechanism of PKM2 involvement in apoptin-mediated cell death in tumor cells. PKM2 expression in lung cancer cells was detected by Western blot and qRT-PCR. In the PKM2 knockdown and over-expression experiments, A549 lung cancer cells were treated with Ad-apoptin, and cell viability was determined by the CCK-8 assay and crystal violet staining. Glycolysis was investigated using glucose consumption and lactate production experiments. Moreover, the effects of Ad-apoptin on autophagy and apoptosis were analyzed by immunofluorescence using the Annexin v-mCherry staining and by western blot for c-PARP, p62, and LC3-II proteins. Immunoprecipitation analysis was used to investigate the interaction between apoptin and PKM2. In addition, following PKM2 knockdown and overexpression, the expression levels of p-AMPK, p-mTOR, p-ULK1, and p-4E-BP1 proteins in Ad-apoptin treated tumor cells were analyzed by western blot to investigate the mechanism of apoptin effect on the energy metabolism of tumor cells. The in vivo antitumor mechanism of apoptin was analyzed by xenograft tumor inhibition experiment in nude mice and immunohistochemistry of tumors' tissue. As a result, apoptin could target PKM2, inhibit glycolysis and cell proliferation in A549 cells, and promote autophagy and apoptosis in A549 cells by regulating the PKM2/AMPK/mTOR pathway. This study confirmed the necessary role of Ad-apoptin in the energy metabolism of A549 cells.

Song G ，Shang C ，Zhu Y ，Xiu Z ，Li Y ，Yang X ，Ge C ，Han J ，Jin N ，Li Y ，Li X ，Fang J ... -  《-》