Identification of the Apoptosis Activation Cascade Induced in Mammary Carcinomas by Energy Restriction

Thompson, Henry J.; Zhu, Zongjian; Jiang, Weiqin

doi:10.1158/0008-5472.can-03-3108

Cited by 36 publications

(23 citation statements)

References 26 publications

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“…This design was chosen based on the fact that at 12 h less than 10% of the cells had entered early apoptosis in response to the combination of both agents. We reasoned that it would be important to define transcriptome changes that occur during the proapoptotic signaling phase rather than those occurring during the execution of the apoptotic program (Castedo et al, 2006;Vitale et al, 2007;de La Motte Rouge et al, 2007), when RNAs (Houge et al, 1995;Nadano and Sato, 2000) and the death-associated bioenergetic collapse (Thompson et al, 2004;Klawitter et al, 2009) (Table 1). The complete list of modified tyrosine kinases is given in Supplementary Table S1.…”

Section: Resultsmentioning

confidence: 99%

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

et al. 2009

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Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up-or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-smallcell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a 'collapse' of pro-survival signal transduction pathways that leads to apoptotic cell death.

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Section: Resultsmentioning

confidence: 99%

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

et al. 2009

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“…BAD stimulates apoptosis by heterodimerizing with and inactivating the antiapoptotic proteins Bcl-2 and Bcl-x (18,19). DR is known to reduce Bcl-2 and Bcl-xL expression and to increase the expression of Bax, Apaf-1, caspase-9, and caspase-3 in experimental carcinomas, suggesting that DR could inhibit tumor growth in part by inducing mitochondrial-dependent apoptosis mediated by the dephosphorylation of BAD (54). Our findings agree with biochemical and morphologic evidence that DR is proapoptotic in malignant astrocytomas and support evidence that BAD coordinates glucose/IGF-I homeostasis and the induction of apoptosis (7,18,19,31).…”

Section: Discussionmentioning

confidence: 99%

Akt-Dependent Proapoptotic Effects of Dietary Restriction on Late-Stage Management of a Phosphatase and Tensin Homologue/Tuberous Sclerosis Complex 2–Deficient Mouse Astrocytoma

Marsh

Mukherjee

Seyfried

2008

Clinical Cancer Research

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Purpose: Malignant astrocytomas exhibit constitutive Akt phosphorylation due to reduced phosphatase and tensin homologue (PTEN) tumor suppressor expression or to increased growth factor receptor tyrosine kinase activation. Many astrocytomas are also tuberous sclerosis complex 2 (TSC2) protein deficient and exhibit constitutive mammalian target of rapamycin (mTOR) activity. Astrocytomas harboring PTEN/Akt/TSC2 pathway mutations are dependent on glycolysis to satisfy their bioenergetic requirements. Therapies that disrupt energy homeostasis can potentially manage astrocytoma growth and progression. Although dietary restriction (DR) reduces glycolysis and manages early-stage astrocytoma growth, no prior studies have identified the mechanisms involved or determined if DR can also manage late-stage tumor growth. Experimental Design: The effects of a late-onset intermittent DR feeding paradigm were examined in adult C57BL/6J mice bearing the syngeneic CT-2A malignant astrocytoma grown orthotopically or subcutaneously. Results: In contrast to contralateral normal brain, CT-2A was PTEN/TSC2 protein deficient; exhibited constitutive Akt, mTOR, and BAD phosphorylation; and overexpressed insulin-like growth factor-I (IGF-I), IGF-I receptor, hypoxia-inducible transcription factor-1a (HIF-1a), type 1 glucose transporter protein (GLUT1), and pyruvate kinase. DR initiated 10 to 14 days after tumor implantation (late onset) reduced CT-2A growth, delayed malignant progression, and significantly extended survival. DR suppressed phosphorylation of Akt and BAD while reducing expression of IGF-I, HIF-1a, and GLUT1. DR also enhanced procaspase-9/procaspase-3 cleavage but had no effect mTOR phosphorylation. Conclusions: Our findings indicate that IGF-I/Akt signaling is associated with the antiapoptotic and glycolytic phenotype of the CT-2A astrocytoma and that DR targets this pathway. Moreover, PTEN/TSC2 deficiency may impair adaptation to the DR-induced disruption of energy homeostasis, thus enhancing apoptosis. Our findings highlight the efficacy of late-onset DR in managing astrocytoma growth and suggest that DR may be an effective broad-spectrum inhibitor of Akt signaling in PTEN/TSC2^deficient astrocytomas.Malignant astrocytomas are the most common primary brain tumors and represent a leading cause of cancer-related deaths in children and the elderly (1 -4). The inability to effectively manage astrocytomas has been due, in part, to the unique anatomic and metabolic environment of the brain that prevents the complete resection of tumor tissue and impedes the delivery of therapeutic agents. Although glucose is the preferred metabolic fuel for healthy neurons and glia, these cells can transition to noncarbohydrate fuels (ketone bodies) for energy under low glucose conditions (5, 6). In contrast, astrocytomas lack metabolic flexibility and are more susceptible than normal brain tissues to cell death mediated by oxidative stress or ATP depletion in response to reduced glucose availability (7 -10). Hence, therapies that can ex...

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“…Indeed, caspase-3 activation and PARP cleavage were undetectable under either ad libitum or DR feeding in the U87-MG tumor. Caspase-3 activation is tightly coupled to PARP cleavage in many tumor cell lines and is important for the rapid onset of apoptosis (25,47). Previous studies showed that expression of active caspase-3 does not overlap completely with that of apoptotic nuclei in various human brain tumors, suggesting the participation of caspase-3-independent cell death pathways in these tumors (22,23,48).…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic and Proapoptotic Effects of Dietary Restriction on Experimental Mouse and Human Brain Tumors

Mukherjee

Abate

Seyfried

2004

Clinical Cancer Research

157

154

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Purpose: The antiangiogenic and proapoptotic mechanisms of dietary caloric restriction (DR) are unknown. In this study, we evaluated the effects of moderate (40%) DR on the orthotopic growth of mouse and human brain tumors that differ in cell origin, angiogenicity, host environment, and biochemical composition.Experimental Design: A malignant mouse astrocytoma (CT-2A) and a human glioma (U87-MG) were highly angiogenic and fast growing, whereas a mouse ependymoblastoma was less vascularized and slower growing. The tumors were evaluated for growth, cell proliferation, microvessel density, and apoptosis under DR and ad libitum feeding. Serum vascular endothelial growth factor and insulin-like growth factor I levels were examined as angiogenic biomarkers.Results: DR significantly decreased vascularity (factor VIII) and increased apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling) in all tumors. These effects were associated with enhanced caspase-3 and poly-(ADP-ribose) polymerase cleavage in the CT-2A and ependymoblastoma tumors, but not in the U87-MG tumor. DR also caused reductions of serum insulin-like growth factor I and glucose levels.Conclusions: DR had significant antiangiogenic and proapoptotic effects in the three distinct brain tumor models. DR, however, had differential effects on cell proliferation, biomarkers of angiogenesis, and apoptosis, suggesting multiple mechanisms of action. Because extensive angiogenesis and resistance to apoptosis are hallmarks of gliomas, this study provides new insight into the molecular basis of the DR-induced inhibition of brain tumor growth.

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Identification of the Apoptosis Activation Cascade Induced in Mammary Carcinomas by Energy Restriction

Cited by 36 publications

References 26 publications

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

Akt-Dependent Proapoptotic Effects of Dietary Restriction on Late-Stage Management of a Phosphatase and Tensin Homologue/Tuberous Sclerosis Complex 2–Deficient Mouse Astrocytoma

Antiangiogenic and Proapoptotic Effects of Dietary Restriction on Experimental Mouse and Human Brain Tumors

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