Type I Interferon Gene Transfer Sensitizes Melanoma Cells to Apoptosis via a Target Activity on Mitochondrial Function

Matarrese, Paola; Biase, Luigi Di; Santodonato, Laura; Straface, Elisabetta; Mecchia, Monica; Ascione, Barbara; Parmiani, Giorgio; Belardelli, Filippo; Ferrantini, Maria; Malorni, Walter

doi:10.1016/s0002-9440(10)62577-1

Cited by 20 publications

(22 citation statements)

References 62 publications

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“…JC-1, a very sensitive reagent largely used to evaluate MMP changes occurring in apoptosis, allows the measurement of both the earlier events (i.e. hyperpolarization) (22) and later events (i.e. depolarization) (18) state of mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Matarrese

Falzano

Fabbri

et al. 2007

Journal of Biological Chemistry

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107

109

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Targeting to mitochondria is emerging as a common strategy that bacteria utilize to interact with these central executioners of apoptosis. Several lines of evidence have in fact indicated mitochondria as specific targets for bacterial protein toxins, regarded as the principal virulence factors of pathogenic bacteria. This work shows, for the first time, the ability of the Clostridium difficile toxin B (TcdB), a glucosyltransferase that inhibits the Rho GTPases, to impact mitochondria. In living cells, TcdB provokes an early hyperpolarization of mitochondria that follows a calcium-associated signaling pathway and precedes the final execution step of apoptosis (i.e. mitochondria depolarization). Importantly, in isolated mitochondria, the toxin can induce a calcium-dependent mitochondrial swelling, accompanied by the release of the proapoptogenic factor cytochrome c. This is consistent with a mitochondrial targeting that does not require the Rho-inhibiting activity of the toxin. Of interest, the mitochondrial ATP-sensitive potassium channels are also involved in the apoptotic response to TcdB and appear to be crucial for the cell death execution phase, as demonstrated by using specific modulators of these channels. To our knowledge, the involvement of these mitochondrial channels in the ability of a bacterial toxin to control cell fate is a hitherto unreported finding.

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Section: Resultsmentioning

confidence: 99%

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Matarrese

Falzano

Fabbri

et al. 2007

Journal of Biological Chemistry

Self Cite

107

109

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“…Human metastatic melanoma cell lines 8863 and 501 have been previously described (10,18). These cell lines were cultured in RPMI 1640 (Life Technologies, Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum (Euroclone), 2 mmol/L glutamine (Sigma), and 50 Ag/mL gentamicin (Sigma).…”

Section: Cell Linesmentioning

confidence: 99%

“…The expression and the activation state of cathepsin B was evaluated by both flow cytometry and Western blot, as previously described (10). For details, see Supplementary Materials and Methods.…”

Section: Analytic Cytology Analysesmentioning

confidence: 99%

“…Cathepsins are released from their physiologic compartment, i.e., the lysosome, and trigger apoptotic cell death via various pathways, including the activation of caspases or the release of proapoptotic factors from the mitochondria. Cathepsin-mediated cell death has been associated with metastatic melanoma since 1986 (9), and we recently showed that this enzymatic cascade was capable of apoptotic induction in cisplatin-treated melanoma cell lines (10).…”

Section: Introductionmentioning

confidence: 99%

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Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism

et al. 2008

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The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the development of resistance to apoptosis. Pyrimethamine belongs to the group of antifolate drugs, and in addition to antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized in human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far. To this end, we examined the in vitro effects of pyrimethamine on apoptosis, cell cycle distribution, and cell proliferation of human metastatic melanoma cell lines. The in vivo antitumor potential of pyrimethamine was evaluated in a severe combined immunodeficiency (SCID) mouse xenotransplantation model. Our data indicate that pyrimethamine, when used at a clinically relevant concentration, induced apoptosis in metastatic melanoma cells via the activation of the cathepsin B and the caspase cascade (i.e., caspase-8 and caspase-9) and subsequent mitochondrial depolarization. This occurred independently from CD95/Fas engagement. Moreover, pyrimethamine induced a marked inhibition of cell growth and an S-phase cell cycle arrest. Results obtained in SCID mice, injected s.c. with metastatic melanoma cells and treated with pyrimethamine, indicated a significant inhibitory effect on tumor growth. In conclusion, our results suggest that pyrimethamine-induced apoptosis may be considered as a multifaceted process, in which different inducers or regulators of apoptosis are simultaneously implicated, thus permitting death defects of melanoma cells to be bypassed or overcome. On these bases, we hypothesize that pyrimethamine could represent an interesting candidate for the treatment of metastatic melanoma.

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“…8 Type I IFNs also directly inhibit proliferation of neoplastic cells through various mechanisms including induction of apoptotic cell death. [10][11][12][13] It has also been reported that activation of DCs with IFN-a or -b leads to upregulation of TNF-a-related apoptosis-inducing ligand (TRAIL) expression, and to direct tumoricidal activity mediated by DCs via TRAIL. 14,15 IFN-a-transduced tumor cells also activate and promote the survival of tumor-specific CD8 + CTLs in vivo.…”

Section: Introductionmentioning

confidence: 99%

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

et al. 2004

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Effective presentation of tumor antigens by dendritic cells (DCs) is considered to be essential for the induction of antitumor T-cell responses. Apoptotic and necrotic tumors have been noted to be a robust antigen source for DCs. Because glioma cells undergo apoptosis after transfection with the type I interferon (IFN) gene and type I IFNs promote the stimulatory activity of DCs, we hypothesized that transfection of glioma cells with type I IFN genes and provision of DCs would promote particularly effective antitumor activity by both facilitating apoptosis of glioma cells and the presentation of the glioma antigens, thereby inducing specific immune responses against glioma cells. We have previously reported the proof of this hypothesis in vitro and in a subcutaneous tumor model. Here we report an extension of this approach in intracranial (i.c.) gliomas using adenoviral IFN-a (Ad-IFN-a) vector. Mice bearing day-5 i.c. GL261 glioma received sequential intratumoral (i.t.) delivery of Ad-IFN-a and bone marrow-derived syngeneic DCs. This treatment prolonged survival in that nine of 17 animals survived long term (460 days versus 0 of 10 control animals). Specific CTL activity was demonstrated following this regimen in the cervical lymph nodes, and the therapeutic efficacy was dependent upon CD8+ cells. Furthermore, these animals were protected against subsequent rechallenge with GL261 gliomas. DCs injected i.t. survived in the tumor and migrated into cervical lymph node. In vitro migration assays revealed the ability of DCs to migrate toward the tumor, suggesting that i.t. injected DCs migrate through the glioma. Taken together, this combination of gene therapy and cellular immunotherapy may be an effective future strategy for treating human gliomas.

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Type I Interferon Gene Transfer Sensitizes Melanoma Cells to Apoptosis via a Target Activity on Mitochondrial Function

Cited by 20 publications

References 62 publications

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

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