A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution

Dolce, Vincenza; Scarcia, Pasquale; Iacopetta, Domenico; Palmieri, Ferdinando

doi:10.1016/j.febslet.2004.12.034

Cited by 203 publications

(185 citation statements)

References 17 publications

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“…25 Four AAC isoforms have been identified in human with distinct expression patterns. 26,27 According to previous reports, [28][29][30] AAC2 and AAC3 are the dominant AACs in ECs. Co-IP confirmed that ISM interacts with AAC2/AAC3 (Figure 5a).…”

Section: Resultsmentioning

confidence: 91%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although avb5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K d ¼ 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

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Section: Resultsmentioning

confidence: 91%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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“…Recent evidence suggests that some ANT isoforms (ANT1, ANT3) are apoptogenic while others are not (ANT2) (Schubert and Grimm, 2004;Zamora et al, 2004). In 2005, a fourth ANT isoform (ANT4) has been identified in man (Dolce et al, 2005) and mouse (Rodic et al, 2005) by means of two independent experimental approaches. The role of this isoform in apoptosis has not been elucidated yet.…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…Of note, we recently reported that ANT2 mRNA is significantly overexpressed in primary tissues derived from patients with cancer of the breast, uterus, ovary, lung, thyroid gland, bladder and testis as compared with the respective normal tissue (Le . These studies preceded the identification of the fourth isoform, ANT4, by real-time quantitative PCR; ANT4 mRNA was only found in healthy human brain, liver and testis (Dolce et al, 2005). It remains to be determined how the expression of the four isoforms varies relative to each other in primary cancer tissues.…”

Section: Expression Of Ant Isoforms In Normal and Cancer Tissuesmentioning

confidence: 99%

“…The ANT4 isoform is anti-apoptotic in human cancer cell lines The ANT4 isoform expression is tightly controlled depending on organism and tissue (Dolce et al, 2005). Interestingly, ANT4 gene is methylated at a long stretch of nucleotides of almost 300 bases just upstream of the predicted transcription initiation site in the promoter region (À212) (Figure 4).…”

Section: Ant1 Isoform Is Pro-apoptotic and Its Expression Is Frequentmentioning

confidence: 99%

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

et al. 2010

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A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution

Cited by 203 publications

References 17 publications

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Mitochondria as therapeutic targets for cancer chemotherapy

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

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