Sublytic complement protects prostate cancer cells from tumour necrosis factor-α-induced cell death

Liu, L.; Li, W.; Li, Z.; Kirschfink, Michael

doi:10.1111/j.1365-2249.2012.04596.x

Cited by 18 publications

(11 citation statements)

References 69 publications

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“…Cross talks between C5b-9 and the various ligands activating RIPK1, RIPK3, and MLKL may, therefore, occur. In agreement, TNFα-mediated CD of carcinoma cells was reduced after a brief pretreatment with a sulytic dose of complement ( 78 ). Similarly, a brief pretreatment with TNFα was shown to protect K562 cells from C5b-9-mediated death ( 79 ).…”

Section: Discussionmentioning

confidence: 56%

Receptor-Interacting Protein Kinases 1 and 3, and Mixed Lineage Kinase Domain-Like Protein Are Activated by Sublytic Complement and Participate in Complement-Dependent Cytotoxicity

et al. 2018

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The complement system participates in the pathogenesis of many diseases. Complement activation produces several active protein complexes and peptides, including the terminal C5b-9 complexes. It was reported that C5b-9 complexes insert into the plasma membrane and cause membrane perturbation, intracellular calcium surge, metabolic depletion, and osmotic lysis. Previously, we showed that complement-dependent cytotoxicity (CDC) is regulated by JNK and Bid. Here, we demonstrate that three mediators in TNFα-induced necroptosis (regulated necrosis), the receptor-interacting protein kinases, receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL), are activated by complement and contribute to CDC. Cell treatment with necrostatin-1 (Nec-1), a RIPK1 inhibitor, GSK’872, a RIPK3 inhibitor, or necrosulfonamide and GW806742X, MLKL inhibitors, restrain CDC. These findings were confirmed by using specific siRNAs targeting the synthesis of these proteins. Mouse fibroblasts lacking RIPK3 or MLKL were found to be less sensitive to C5b-9 than were wild-type (WT) fibroblasts. Enhanced CDC was achieved by RIPK1 or RIPK3 overexpression but not by the overexpression of a RHIM-RIPK1 mutant nor by a kinase-dead RIPK3 mutant. Nec-1 reduces the CDC of WT but not of RIPK3-knockout fibroblasts. Cells treated with a sublytic dose of complement exhibit co-localization of RIPK3 with RIPK1 in the cytoplasm and co-localization of RIPK3 and MLKL with C5b-9 at the plasma membrane. Data supporting cooperation among the RIP kinases, MLKL, JNK, and Bid in CDC are presented. These results provide a deeper insight into the cell death process activated by complement and identify potential points of cross talk between complement and other inducers of inflammation and regulated necrosis.

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Section: Discussionmentioning

confidence: 56%

Receptor-Interacting Protein Kinases 1 and 3, and Mixed Lineage Kinase Domain-Like Protein Are Activated by Sublytic Complement and Participate in Complement-Dependent Cytotoxicity

et al. 2018

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“…Our results suggest that overexpressing FAM3B promotes survival in DU145/FAM3B cells through increased Bcl-2 and Bcl-X L expression and inhibition of caspase-3 cleavage. It is known that TNF-α can trigger both NF-κB and apoptosis signaling simultaneously, so suppression of TNF-α-induced NF-κB signaling by CHX is expected to potentiate TNF-α induced apoptosis through caspase-3, whereas overexpression of Bcl-2 and Bcl-X L would inhibit this same activation [ 14 , 23 ]. Although the inhibition of caspase activity was observed only after TNF-α treatment it is reasonable to propose that FAM3B might directly or indirectly upregulate the anti-apoptotic caspase inhibitors, such as survivin, with ensuing resistance to cell death.…”

Section: Discussionmentioning

confidence: 99%

FAM3B/PANDER inhibits cell death and increases prostate tumor growth by modulating the expression of Bcl-2 and Bcl-XL cell survival genes

et al. 2018

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BackgroundFAM3B/PANDER is a novel cytokine-like protein that induces apoptosis in insulin-secreting beta-cells. Since in silico data revealed that FAM3B can be expressed in prostate tumors, we evaluated the putative role of this cytokine in prostate tumor progression.MethodsFAM3B expression was analyzed by quantitative PCR in tumor tissue clinical samples and prostate tumor cell lines. Culture growth and viability of DU145 cell line were evaluated after treatment with either exogenous FAM3B protein obtained from conditioned media (CM) of 293 T cells overexpressing FAM3B or a recombinant FAM3B protein produced in a bacterial host. DU145 cells overexpressing FAM3B protein were produced by lentiviral-mediated transduction of full-length FAM3B cDNA. Cell viability and apoptosis were analyzed in DU145/FAM3B cells after treatment with several cell death inducers, such as TNF-alpha, staurosporine, etoposide, camptothecin, and serum starvation conditions. Anchorage-independent growth in soft agarose assay was used to evaluate in vitro tumorigenicity. In vivo tumorigenicity and invasiveness were evaluated by tumor xenograft growth in nude mice.ResultsWe observed an increase in FAM3B expression in prostate tumor samples when compared to normal tissues. DU145 cell viability and survival increased after exogenous treatment with recombinant FAM3B protein or FAM3B-secreted protein. Overexpression of FAM3B in DU145 cells promoted inhibition of DNA fragmentation and phosphatidylserine externalization in a time and dose-dependent fashion, upon apoptosis triggered by TNF-alpha. These events were accompanied by increased gene expression of anti-apoptotic Bcl-2 and Bcl-XL, decreased expression of pro-apoptotic Bax and diminished caspase-3, −8 and −9 proteolytic activities. Furthermore, inhibition of Bcl-2 anti-apoptotic family proteins with small molecules antagonists decreases protective effects of FAM3B in DU145 cells. When compared to the respective controls, cells overexpressing FAM3B displayed a decreased anchorage- independent growth in vitro and increased tumor growth in xenografted nude mice. The immunohistochemistry analysis of tumor xenografts revealed a similar anti-apoptotic phenotype displayed by FAM3B-overexpressing tumor cells.ConclusionsTaken together, by activating pro-survival mechanisms FAM3B overexpression contributes to increased resistance to cell death and tumor growth in nude mice, highlighting a putative role for this cytokine in prostate cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3950-9) contains supplementary material, which is available to authorized users.

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“…Very limited data is available for complement and prostate cancer. Sublytic complement C5b-9 protects prostate cancer cells from tumour necrosis factor-α-induced cell death 82 . Interestingly, proteolysis of iC3b and C5 by the serine protease prostate-specific antigen in prostatic fluid was detected, inhibiting the terminal pathway 83 .…”

Section: Cancers With "Protective Complement"mentioning

confidence: 99%

Context-dependent roles of complement in cancer

et al. 2019

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The tumor microenvironment (TME) highly influences the growth, spreading of tumors and therefore patient's clinical outcome. In this context, complement system plays a major and complex role. It may either kill antibody-coated tumor cells or support local inflammation, hamper anti-tumor T cell responses favoring cancer spreading. Recent studies demonstrate that these opposite effects depend of the sites of its activation, the composition of the TME and the tumor cell sensitivity to complement attack. In this review, we present the implication of complement activation and its effects on cancer control and clinical outcome in different TME contexts. We also provide an overview of the publicly available transcriptomic data on the prognostic value of complement genes expression in 30 cancer types. We argue that the interplay of complement within each cancer is unique, governed by the properties of the tumor cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies.

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Sublytic complement protects prostate cancer cells from tumour necrosis factor-α-induced cell death

Cited by 18 publications

References 69 publications

Receptor-Interacting Protein Kinases 1 and 3, and Mixed Lineage Kinase Domain-Like Protein Are Activated by Sublytic Complement and Participate in Complement-Dependent Cytotoxicity

Receptor-Interacting Protein Kinases 1 and 3, and Mixed Lineage Kinase Domain-Like Protein Are Activated by Sublytic Complement and Participate in Complement-Dependent Cytotoxicity

FAM3B/PANDER inhibits cell death and increases prostate tumor growth by modulating the expression of Bcl-2 and Bcl-XL cell survival genes

Context-dependent roles of complement in cancer

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