BiP/GRP78 Is an Intracellular Target for MDA-7/IL-24 Induction of Cancer-Specific Apoptosis

Gupta, Pankaj; Walter, Mark R.; Su, Zhao Zhong; Lebedeva, Irina V.; Emdad, Luni; Randolph, Aaron; Valerie, Kristoffer; Sarkar, Devanand; Fisher, Paul B.

doi:10.1158/0008-5472.can-06-0577

Cited by 112 publications

(142 citation statements)

References 34 publications

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“…These results support the notion that BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. 49 Collectively, our data indicate that the activation of PKR, p38 MAPK and induction of ER stress could be involved in ZD55-IL-24-induced leukemia apoptotic cell death.…”

Section: Discussionmentioning

confidence: 69%

Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis

et al. 2007

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Conditionally replicating adenoviruses (CRAds) represent a promising new platform for anticancer therapy. However, CRAds have been evaluated little in hematopoietic malignancies because of the lack of expression of coxsackie adenovirus receptor (CAR) on their cell surface. In this study, we showed that CAR was expressed on two types of lymphoblastic leukemia cell lines and primary leukemia cells, and that ZD55, a CRAd, exerted a potent antileukemia effect in vitro and in vivo. Furthermore, ZD55 expressing melanoma differentiation-associated gene-7/interleukin-24 (ZD55-IL-24) elicited significant enhanced antileukemia activity comparing with ZD55, concomitant with upregulation of RNA-dependent protein kinase R (PKR), increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), and induction of endoplasmic reticulum (ER) stress. These data for the first time indicate that MDA-7/IL-24 exerts its antitumor effect on leukemia cells via multiple pathways, and suggest that oncolytic adenoviruses, ZD55 and ZD55-IL-24 could potentially be used against CAR-expressing hematological malignancies such as B-lymphoblastic leukemia/ lymphoma and some myeloid leukemia.

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Section: Discussionmentioning

confidence: 69%

Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis

et al. 2007

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“…We reported that Ad.mda-7 induces an UPR pathway (17,18,24). The robust expression of MDA-7/IL-24 protein and the subsequent killing effect suggest that similar to Ad.mda-7, MDA-7/IL-24 may induce an UPR pathway.…”

Section: Mda-7/il-24 Protein Stimulates the Upr Pathway And Generatesmentioning

confidence: 90%

“…The successful transition of Ad.mda-7 into the clinic in a phase I clinical trial reinforces the hypothesis that mda-7/IL-24 is safe and affords remarkable potential as a cancer gene therapeutic. Moreover, secreted MDA-7/IL-24 protein, generated from Ad.mda-7-infected cells, promotes antiangiogenic, immunostimulatory, radiosensitizing and ''bystander'' antitumor activities (6,11,17,18).…”

mentioning

confidence: 99%

“…IP3R is an intracellular calcium-release channel implicated in apoptosis and localized in the ER. Hsp70-like chaperone (BiP/ GRP78)-binding sites are present in helices C and F of MDA-7/ IL-24, and mutations in these sites prevent this cytokine from inducing cancer cell-specific apoptosis (17). Additionally, a microarray study indicated that mda-7/IL-24 is able to induce the expression of ER stress response genes, including BiP/GRP78.…”

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confidence: 99%

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Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Sauane¹,

Gupta³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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A noteworthy aspect of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) as a cancer therapeutic is its ability to selectively kill cancer cells without harming normal cells. Intracellular MDA-7/IL-24 protein, generated from an adenovirus expressing mda-7/IL-24 (Ad.mda-7), induces cancerspecific apoptosis by inducing an endoplasmic reticulum (ER) stress response. Secreted MDA-7/IL-24 protein, generated from cells infected with Ad.mda-7, induces growth inhibition and apoptosis in surrounding noninfected cancer cells but not in normal cells, thus exerting an anti-tumor ''bystander'' effect. The present studies reveal a provocative finding that recombinant MDA-7/IL-24 protein can robustly induce expression of endogenous mda-7/IL-24, which generates the signaling events necessary for bystander killing. To evaluate the mechanism underlying this positive autocrine feedback loop, we show that MDA-7/IL-24 protein induces stabilization of its own mRNA without activating its promoter. Furthermore, this posttranscriptional effect depends on de novo protein synthesis. As a consequence of this autocrine feedback loop MDA-7/IL-24 protein induces sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, GADD153, and phosphoeIF2␣) and reactive oxygen species production, indicating that both intracellular and secreted proteins activate similar signaling pathways to induce apoptosis. Thus, our results clarify the molecular mechanism by which secreted MDA-7/IL-24 protein (generated from Ad.mda-7-infected cells) exerts cancer-specific killing.bystander antitumor activity ͉ endoplasmic reticulum stress ͉ reactive oxygen species ͉ mRNA stabalization ͉ cancer-specific killing

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“…15,20,23 After Ad.mda-7 infection, the MDA-7/IL-24 protein interacts with the endoplasmic reticulum (ER) chaperone protein BiP/GRP78 and initiates a cascade of "unfolded protein response (UPR)/ER-stress response" events in tumor cells resulting in the activation of p38 MAPK and induction of growth arrest and DNA damage inducible (GADD) genes that culminate in apoptosis. [32][33][34] Interestingly, although MDA-7/IL-24 is localized in the ER in both normal and cancer cells, the ER-stress response-induced apoptosis induction is observed only in cancer cells of diverse tissue origin, but not in their normal counterparts. Recent findings show that the level of BiP/GRP78 is higher in multiple cancer cells than in normal cells, which might make cancer cells more susceptible to ER stress by mda-7/IL-24.…”

Section: Diverse Molecular and Signal Transduction Pathways Involved mentioning

confidence: 99%

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Emdad

Lebedeva

et al. 2009

Cancer Biology & Therapy

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A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells. Unique properties of mda-7/IL-24 action also include potent "bystander antitumor" activity, an ability to exert anti-angiogenic effects, immune modulating ability and a capacity to enhance the sensitivity of tumor cells to radiotherapy, chemotherapy and monoclonal antibody therapy. Very recent studies from our groups further reveal autocrine regulation and chemoprevention facilitating properties of mda-7/IL-24. Based on these remarkable antitumor attributes, mda-7/IL-24 was evaluated by intratumoral injection with a replication incompetent adenovirus expressing this gene (Ad.mda-7; INGN 241) in a phase I clinical trial in patients with metastatic melanomas and other advanced solid cancers. mda-7/IL-24 was well tolerated with significant clinical activity. This review highlights our current understanding of the molecular and biochemical basis of mda-7/IL-24 antitumor properties and highlights its potential as a viable gene-based therapy for a wide spectrum of primary and advanced cancers.

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BiP/GRP78 Is an Intracellular Target for MDA-7/IL-24 Induction of Cancer-Specific Apoptosis

Cited by 112 publications

References 34 publications

Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis

Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

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