Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment.

Apoptosis, an important form of programmed cell death (PCD), is a tightly regulated cellular process to eliminate unwanted or damaged cells. Resistance of apoptosis is a hallmark of cancer cells. I...

Inhibitor of Apoptosis Protein (IAP) Antagonists in Anticancer Agent Discovery: Current Status and Perspectives.

While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer.

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Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy

Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.

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Glucose Metabolism and Glucose Transporters in Breast Cancer

Vitamin K2 has been shown to exert remarkable anticancer activity. However, the detailed mechanism remains unclear. Here, our study was the first to show that Vitamin K2 significantly promoted the glycolysis in bladder cancer cells by upregulating glucose consumption and lactate production, whereas inhibited TCA cycle by reducing the amounts of Acetyl-CoA. Moreover, suppression of PI3K/AKT and HIF-1α attenuated Vitamin K2-increased glucose consumption and lactate generation, indicating that Vitamin K2 promotes PI3K/AKT and HIF-1α-mediated glycolysis in bladder cancer cells. Importantly, upon glucose limitation, Vitamin K2-upregulated glycolysis markedly induced metabolic stress, along with AMPK activation and mTORC1 pathway suppression, which subsequently triggered AMPK-dependent autophagic cell death. Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death. Furthermore, both inhibition of PI3K/AKT/HIF-1α and attenuation of glycolysis significantly blocked Vitamin K2-induced AMPK activation and subsequently prevented autophagic cell death. Collectively, these findings reveal that Vitamin K2 could induce metabolic stress and trigger AMPK-dependent autophagic cell death in bladder cancer cells by PI3K/AKT/HIF-1α-mediated glycolysis promotion.

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Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells.

Previous studies have indicated that the sensitivity of breast cancer cells to tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL)‑induced apoptosis is associated with the expression of death receptors on the cell membrane. However, drug resistance limits the use of TRAIL in cancer therapy. Numerous studies have indicated that death receptors, which induce apoptosis, are upregulated by the endoplasmic reticulum (ER) stress response. 3‑Bromopyruvate (3‑BP), an anticancer agent, inhibits cell growth and induces apoptosis through interfering with glycolysis. In the present study, it was demonstrated that 3‑BP synergistically sensitized breast cancer cells to TRAIL‑induced apoptosis via the upregulation of death receptor 5 (DR5). Furthermore, we found that the protein levels of glucose‑related protein 78 (GRP78) and CCAAT‑enhancer‑binding protein homologous protein (CHOP) increased following treatment with 3‑BP. The expression of Bax (in MCF‑7 cells) and caspase‑3 (in MDA‑MB‑231 cells) increased following co‑treatment with 3‑BP and TRAIL, whereas the expression of the anti‑apoptotic protein Bcl‑2 decreased. In order to investigate the molecular mechanism regulating this effect, the expression of adenosine monophosphate‑activated protein kinase (AMPK), activated by 3‑BP, was determined. It was demonstrated that phosphorylated‑AMPK was upregulated following treatment with 3‑BP. Notably, Compound C, an AMPK inhibitor, reversed the effects of 3‑BP. Finally, a synergistic antitumor effect of 3‑BP and TRAIL was observed in MCF‑7 cell xenografts in nude mice. In conclusion, these results indicated that 3‑BP sensitized breast cancer cells to TRAIL via the AMPK‑mediated upregulation of DR5.

/pdf/3-bromopyruvate-sensitizes-human-breast-cancer-cells-to-21z9ilpdnf.pdf

3‑Bromopyruvate sensitizes human breast cancer cells to TRAIL‑induced apoptosis via the phosphorylated AMPK‑mediated upregulation of DR5

There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial‑derived activator of caspase/direct IAP‑binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA‑MB‑231 and MCF‑7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161‑dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor‑interacting protein kinase‑1 via small interfering RNA protected the cells from LCL161‑induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds.

/pdf/smac-mimetic-induced-caspase-independent-necroptosis-2r3vs54qwn.pdf

Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer

Background Sepiapterin reductase (SPR) is an important regulator of the biosynthesis of tetrahydrobiopterin (BH4), which has been shown to be a promoter of different kinds of tumors. This study aims to investigate the role of SPR in breast cancer and to explore its molecular mechanism. Methods SPR expressions in breast cancer tissues with different pathological stages were compared with the corresponding pericarcinomatous tissues and were analyzed using immunohistochemical staining and western blot. SPR knockdown was performed in MDA-MB-231 and MDA-MB-468 triple-negative breast cancer cells using specific siRNAs. Quantitative real-time PCR and western blot were used to determine the efficiency of the SPR knockdown. The intracellular BH4 levels were measured using HPLC, and the intracellular ROS levels were measured using an ROS detection kit. Clone formation and cell proliferation assays were used to study the effect of the SPR knockdown on cell proliferation. Annexin V/PI double staining, cell mitochondria isolation, and western blot were performed to study the effect of the SPR knockdown on cell apoptosis. ROS scavenger NAC was used to inhibit increased ROS caused by the SPR knockdown. Results SPR is highly expressed in breast cancer tissues compared with the pericarcinomatous tissues and positively correlated with the pathological stages. The knockdown of SPR causes decreased intracellular BH4 and increased intracellular ROS and inhibits the proliferation of MDA-MB-231 and MDA-MB-468 cells. The knockdown of SPR also induces mitochondrial pathway-mediated apoptosis. NAC suppresses the SPR knockdown-caused cell apoptosis and cell death. Conclusions SPR promotes the proliferation of breast cancer cells. The knockdown of SPR suppresses the proliferation of breast cancer cells by inducing ROS-mediated apoptosis.

The knockdown of the sepiapterin reductase gene suppresses the proliferation of breast cancer by inducing ROS-mediated apoptosis.

This study aimed to investigate the anti-cancer effect of lobetyolin on breast cancer cells. Lobetyolin was incubated with MDA-MB-231 and MDA-MB-468 breast cancer cells for 24 h. Glucose uptake and the mRNA expression of GLUT4 (SLC2A4), HK2 and PKM2 were detected to assess the effect of lobetyolin on glucose metabolism. Glutamine uptake and the mRNA expression of ASCT2 (SLC1A5), GLS1, GDH and GLUL were measured to assess the effect of lobetyolin on glutamine metabolism. Annexin V/PI double staining and Hoechst 33342 staining were used to investigate the effect of lobetyolin on cell apoptosis. Immunoblot was employed to estimate the effect of lobetyolin on the expression of proliferation-related markers and apoptosis-related markers. SLC1A5 knockdown with specific siRNA was performed to study the role of ASCT2 played in the anti-cancer effect of lobetyolin on MDA-MB-231 and MDA-MB-468 breast cancer cells. C-MYC knockdown with specific siRNA was performed to study the role of c-Myc played in lobetyolin-induced ASCT2 down-regulation. Myr-AKT overexpression was performed to investigate the role of AKT/GSK3β signaling played in lobetyolin-induced down-regulation of c-Myc and ASCT2. The results showed that lobetyolin inhibited the proliferation of both MDA-MB-231 and MDA-MB-468 breast cancer cells. Lobetyolin disrupted glutamine uptake via down-regulating ASCT2. SLC1A5 knockdown attenuated the anti-cancer effect of lobetyolin. C-MYC knockdown attenuated lobetyolin-caused down-regulation of ASCT2 and Myr-AKT overexpression reversed lobetyolin-caused down-regulation of both c-Myc and ASCT2. In conclusion, the present work suggested that lobetyolin exerted anti-cancer effect via ASCT2 down-regulation-induced apoptosis in breast cancer cells.

Xianfu Liu

Papers

3‑Bromopyruvate sensitizes human breast cancer cells to TRAIL‑induced apoptosis via the phosphorylated AMPK‑mediated upregulation of DR5

Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer

The knockdown of the sepiapterin reductase gene suppresses the proliferation of breast cancer by inducing ROS-mediated apoptosis.

Lobetyolin inhibits the proliferation of breast cancer cells via ASCT2 down-regulation-induced apoptosis.