SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events

Yu, Jian; Wang, P; Ming, Lihua; Wood, Marcelo A.; Zhang, Lin

doi:10.1038/sj.onc.1210196

Cited by 72 publications

(68 citation statements)

References 40 publications

(56 reference statements)

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“…Our data extend these findings to melanoma and mastocytoma cells, which is of importance as it has been suggested that the role of SMAC can vary depending on the cell type (27). Of note, we achieved substantial induction of cell death using an MOI as low as 1.…”

Section: Discussionsupporting

confidence: 67%

Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy

et al. 2012

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Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LVtSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high lytic capacity, and high levels of IFN-g when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8 þ T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumorspecific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer. Cancer Res; 72(6);

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Section: Discussionsupporting

confidence: 67%

Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy

et al. 2012

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“…PUMA binds to antiapoptotic Bcl-2 family members to activate the proapoptotic members Bax and Bak to trigger mitochondrial dysfunction. This results in the release of several apoptogenic mitochondrial proteins, such as cytochrome c and SMAC, leading to caspase activation and cell death (15,16). Knockout of PUMA in human colon cancer cells or in mice leads to resistance to apoptosis induced by a number of stimuli, such as DNA damage, kinase inhibition, oncogene activation, and endoplasmic reticulum stress (13).…”

Section: Introductionmentioning

confidence: 99%

PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

Qiu

Wu²,

Wang³

et al. 2011

J. Clin. Invest.

162

157

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Intestinal epithelial cell (IEC) apoptosis contributes to the development of ulcerative colitis (UC), an inflammatory bowel disease (IBD) that affects the colon and rectum. Therapies that target the inflammatory cytokine TNF have been found to inhibit IEC apoptosis in patients with IBD, although the mechanism of IEC apoptosis remains unclear. We therefore investigated the role of p53-upregulated modulator of apoptosis (PUMA), a p53 target and proapoptotic BH3-only protein, in colitis and IEC apoptosis, using patient samples and mouse models of UC. In UC patient samples, PUMA expression was elevated in colitis tissues relative to that in uninvolved tissues, and the degree of elevation of PUMA expression correlated with the severity of colitis and the degree of apoptosis induction. In mice, PUMA was markedly induced in colonic epithelial cells following induction of colitis by either dextran sulfate sodium salt (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). The induction of PUMA was p53-independent but required NF-κB. Absence of PUMA, but neither absence of p53 nor that of another BH3-only protein (Bid), relieved DSS-and TNBS-induced colitis and inhibited IEC apoptosis. Furthermore, treating mice with infliximab (Remicade), a clinically used TNF-specific antibody, suppressed DSS-and TNBS-induced PUMA expression and colitis. These results indicate that PUMA induction contributes to the pathogenesis of colitis by promoting IEC apoptosis and suggest that PUMA inhibition may be an effective strategy to promote mucosal healing in patients with UC.

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“…The combination of Smac activation with classical anticancer drugs seems to be a rational therapeutic approach (15,16). Overexpression of Smac and chemically synthesized Smac mimetics can enhance apoptosis induced by chemotherapy and radiotherapy in several types of tumor cells (12,13,(17)(18)(19)(20)(21). Smac expression has been detected in a variety of normal and tumor tissues, but the expression varies among different tumor types (22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11]. Recent work suggests that Smacmediated apoptosis is important for the apoptotic responses induced by several anticancer agents, including certain chemopreventive agents (10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma

Zhou

Huang

et al. 2011

Clinical Cancer Research

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Purpose: Second mitochondria-derived activator of caspase (Smac) regulates chemotherapy-induced apoptosis. Smac mimetics have been tested in clinical trials as chemosensitizers. We determined the role of Smac in modulating the chemosensitivity of esophageal squamous cell carcinoma (ESCC).Experimental Design: Smac expression was evaluated in tissues from ESCC patients with differential chemotherapeutic responses. The effects of Smac knockdown and Smac mimetics on the chemosensitivity of ESCC cells and the molecular mechanisms by which Smac and Smac mimetics modulate chemosensitivity were determined. The therapeutic responses of ESCC cells with different Smac statuses were compared using xenograft models.Results: We found that Smac was significantly downregulated in most ESCC samples (36.8%, 25/68, P ¼ 0.001), and Smac expression differed significantly (P < 0.05) between chemosensitive and chemoresistant tumors. The associations of tested factors and their responses were examined using logistic regression analysis. In ESCC cells treated with cisplatin, a common chemotherapeutic drug, Smac and cytochrome c were released from mitochondria, and caspase-3 and caspase-9 were activated.

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SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events

Cited by 72 publications

References 40 publications

Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy

Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy

PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma

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