LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis
TL;DR: The results suggested that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.
Abstract: LDH-A, as the critical enzyme accounting for the transformation from pyruvate into lactate, has been demonstrated to be highly expressed in various cancer cells and its silencing has also been approved relating to increased apoptosis in lymphoma cells. In this study, we intend to investigate the correlation between LDH-A and other clinicopathological factors of breast cancer and whether LDH-A silencing could suppress breast cancer growth, and if so the potential mechanisms. 46 breast cancer specimens were collected to study the relation between LDH-A expression and clinicopathological characteristics including menopause, tumor size, node involvement, differentiation, and pathological subtypes classified by ER, PR, and Her-2. shRNAs were designed and applied to silence LDH-A expression in breast cancer cell lines MCF-7 and MDA-MB-231. The effects of LDH-A reduction on cancer cells were studied by a series of in vitro and in vivo experiments, including cell growth assay, apoptosis evaluation, oxidative stress detection, transmission electron microscopy observation, and tumor formation assay on nude mice. LDH-A expression was found to correlate significantly with tumor size and to be independent for other clinicopathological factors. LDH-A reduction resulted in an inhibited cancer cell proliferation, elevated intracellular oxidative stress, and induction of mitochondrial pathway apoptosis. Meanwhile, the tumorigenic ability of LDH-A deficient cancer cells was significantly limited in both breast cancer xenografts. The Ki67 positive cancer cells were significantly reduced in LDH-A deficiency tumor samples, while the apoptosis ratio was enhanced. Our results suggested that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.
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TL;DR: Because of the reliance of MYC-driven cancers on specific metabolic pathways, synthetic lethal interactions between MYC overexpression and specific enzyme inhibitors provide novel cancer therapeutic opportunities.
Abstract: The MYC oncogene encodes a transcription factor, MYC, whose broad effects make its precise oncogenic role enigmatically elusive. The evidence to date suggests that MYC triggers selective gene expression amplification to promote cell growth and proliferation. Through its targets, MYC coordinates nutrient acquisition to produce ATP and key cellular building blocks that increase cell mass and trigger DNA replication and cell division. In cancer, genetic and epigenetic derangements silence checkpoints and unleash MYC9s cell growth– and proliferation-promoting metabolic activities. Unbridled growth in response to deregulated MYC expression creates dependence on MYC-driven metabolic pathways, such that reliance on specific metabolic enzymes provides novel targets for cancer therapy. Significance: MYC9s expression and activity are tightly regulated in normal cells by multiple mechanisms, including a dependence upon growth factor stimulation and replete nutrient status. In cancer, genetic deregulation of MYC expression and loss of checkpoint components, such as TP53, permit MYC to drive malignant transformation. However, because of the reliance of MYC-driven cancers on specific metabolic pathways, synthetic lethal interactions between MYC overexpression and specific enzyme inhibitors provide novel cancer therapeutic opportunities. Cancer Discov; 5(10); 1024–39. ©2015 AACR.
833 citations
TL;DR: Key genes involved in ribosomal and mitochondrial biogenesis, glucose and glutamine metabolism, lipid synthesis, and cell-cycle progression are robustly activated by MYC, contributing to the acquisition of bioenergetics substrates for the cancer cell to grow and proliferate.
Abstract: The MYC proto-oncogene is frequently activated in human cancers through a variety of mechanisms. Its deregulated expression, unconstrained by inactivation of key checkpoints, such as p53, contributes to tumorigenesis. Unlike its normal counterpart, which is restrained by negative regulators, the unleashed MYC oncogene produces a transcription factor that alters global gene expression through transcriptional regulation, resulting in tumorigenesis. Key genes involved in ribosomal and mitochondrial biogenesis, glucose and glutamine metabolism, lipid synthesis, and cell-cycle progression are robustly activated by MYC, contributing to the acquisition of bioenergetics substrates for the cancer cell to grow and proliferate.
522 citations
Cites background from "LDH-A silencing suppresses breast c..."
...Knockdown of lactate dehydrogenase A (LDHA), which converts pyruvate to lactate, significantly curbed the clonogenicity of lymphoma cells and inhibited tumorigenicity of mammary cancer, lung cancer, and neuroblastomas with amplified NMYC in mice (Shim et al. 1997; Fantin et al. 2006; Xie et al. 2009; Le et al. 2010; Qing et al. 2010; Wang et al. 2012)....
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...…pyruvate to lactate, significantly curbed the clonogenicity of lymphoma cells and inhibited tumorigenicity of mammary cancer, lung cancer, and neuroblastomas with amplified NMYC in mice (Shim et al. 1997; Fantin et al. 2006; Xie et al. 2009; Le et al. 2010; Qing et al. 2010; Wang et al. 2012)....
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TL;DR: It is demonstrated that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors, and LDH -A can be a viable therapeutic target forNSCLC, including cancer stem cell-dependent drug-resistant tumors.
399 citations
Cites result from "LDH-A silencing suppresses breast c..."
...Previous work from others and us has shown that that LDH-A-suppressed cancer cell lines exhibit reduced tumor progression in xenograft models (Fan et al., 2011a; Fantin et al., 2006; Wang et al., 2012)....
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TL;DR: There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months.
Abstract: There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.
375 citations
Cites background from "LDH-A silencing suppresses breast c..."
...In vivo xenografts of breast cancer cell lines also found that cell lines with LDHA knocked down had elevated Bax, cleaved PARP, cleaved caspase-9, cytosolic cytochrome C and superoxide anion expression but decreased Bcl-2 expression and mitochondrial membrane potential (137)....
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...Multiple in vitro and in vivo xenograft mouse model studies have found that LDHA knockdown cells treated with N-acetyl-L-cysteine (NAC), an antioxidant that breaks disulfide bonds, prevented or partially prevented the induced generation of ROS and apoptosis (113, 137, 140)....
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TL;DR: In conclusion, what is discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.
Abstract: Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio-characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.
313 citations
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TL;DR: The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation, and reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
Abstract: Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
2,423 citations
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..., by the so-called quick score (Q) (Q = P 9 I; maximum = 300) [22]....
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TL;DR: The increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of Glycolysis.
Abstract: Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.
1,403 citations
"LDH-A silencing suppresses breast c..." refers background in this paper
...Besides hexokinase, G6PD, GAPDH, and TKTL1 were also well demonstrated in laboratory to be potential targets [6]....
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...Some key enzymes in the process have already become molecular targets, and corresponding inhibitors have demonstrated significant anti-cancer effects and have been approved for clinical trials [6]....
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