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A possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma.

ABSTRACT: Melanoma is the most aggressive form of skin cancer, responsible for the majority of skin cancer related deaths. Thus, the search for natural molecules which can effectively destroy tumors while promoting immune activation is essential for designing novel therapies against metastatic melanoma. Here, we report for the first time that a natural triterpenoid, Ganoderic acid DM (GA-DM), induces an orchestrated autophagic and apoptotic cell death, as well as enhanced immunological responses via increased HLA class II presentation in melanoma cells. Annexin V staining and flow cytometry showed that GA-DM treatment induced apoptosis of melanoma cells, which was supported by a detection of increased Bax proteins, co-localization and elevation of Apaf-1 and cytochrome c, and a subsequent cleavage of caspases 9 and 3. Furthermore, GA-DM treatment initiated a possible cross-talk between autophagy and apoptosis as evidenced by increased levels of Beclin-1 and LC3 proteins, and their timely interplay with apoptotic and/or anti-apoptotic molecules in melanoma cells. Despite GA-DM's moderate cytotoxicity, viable cells expressed high levels of HLA class II proteins with improved antigen presentation and CD4+ T cell recognition. The antitumor efficacy of GA-DM was also investigated in vivo in murine B16 melanoma model, where GA-DM treatment slowed tumor formation with a significant reduction in tumor volume. Taken together, these findings demonstrate the potential of GA-DM as a natural chemo-immunotherapeutic capable of inducing a possible cross-talk between autophagy and apoptosis, as well as improved immune recognition for sustained melanoma tumor clearance.

SUBMITTER: Hossain A

PROVIDER: S-EPMC3747633 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma.

Hossain Azim A Radwan Faisal F Y FF Doonan Bently P BP God Jason M JM Zhang Lixia L Bell P Darwin PD Haque Azizul A

Apoptosis : an international journal on programmed cell death 20121001 10

Melanoma is the most aggressive form of skin cancer, responsible for the majority of skin cancer related deaths. Thus, the search for natural molecules which can effectively destroy tumors while promoting immune activation is essential for designing novel therapies against metastatic melanoma. Here, we report for the first time that a natural triterpenoid, Ganoderic acid DM (GA-DM), induces an orchestrated autophagic and apoptotic cell death, as well as enhanced immunological responses via incre ...[more]

PMID: 22847295

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Project description:Unresectable colorectal liver metastases remain a major unresolved issue and more effective novel regimens are urgently needed. While screening synergistic drug combinations for colon cancer therapy, we identified a novel multidrug treatment for colon cancer: chemotherapeutic agent melphalan in combination with proteasome inhibitor bortezomib and mTOR (mammalian target of rapamycin) inhibitor rapamycin. We investigated the mechanisms of synergistic antitumor efficacy during the multidrug treatment. All experiments were performed with highly metastatic human colon cancer CX-1 and HCT116 cells, and selected critical experiments were repeated with human colon cancer stem Tu-22 cells and mouse embryo fibroblast (MEF) cells. We used immunochemical techniques to investigate a cross-talk between apoptosis and autophagy during the multidrug treatment. We observed that melphalan triggered apoptosis, bortezomib induced apoptosis and autophagy, rapamycin caused autophagy and the combinatorial treatment-induced synergistic apoptosis, which was mediated through an increase in caspase activation. We also observed that mitochondrial dysfunction induced by the combination was linked with altered cellular metabolism, which induced adenosine monophosphate-activated protein kinase (AMPK) activation, resulting in Beclin-1 phosphorylated at Ser 93/96. Interestingly, Beclin-1 phosphorylated at Ser 93/96 is sufficient to induce Beclin-1 cleavage by caspase-8, which switches off autophagy to achieve the synergistic induction of apoptosis. Similar results were observed with the essential autophagy gene, autophagy-related protein 7, -deficient MEF cells. The multidrug treatment-induced Beclin-1 cleavage was abolished in Beclin-1 double-mutant (D133A/D146A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. These observations identify a novel mechanism for AMPK-induced apoptosis through interplay between autophagy and apoptosis.

Project description:Circular RNAs (circRNAs) have emerged as a new type of endogenous non-coding RNA characterized by their covalently closed circular structure and a backspliced junction (BSJ) resulting from a back-splicing process. In the last years, several studies have shown that circRNAs are important modulators in the immune system, activation of inflammation, antibacterial and antiviral responses as well as autoimmune diseases, such as multiple sclerosis. In the last years, it has been proposed that a subset of circRNA form imperfect double-stranded structures that allow them to interact with PKR (double stranded RNA-activated protein kinase), an intracellular protein responsible for recognizing long double stranded RNAs, usually viral RNAs, in the cytoplasm and trigger an anti-viral response of the cell. Taking into account the implication of the innate immune response in multiple sclerosis pathophysiology and the discovery of circRNA deregulation in multiple sclerosis patients, we wanted to investigate the circRNA-PKR crosstalk and its implication in the pathology of multiple sclerosis. Using an in vitro model of the anti-viral response and RNA-seq to characterize circRNA expression, we observed that poly (I:C) (a double-stranded RNA) stimulation produces a global downregulation of circRNA, PKR phosphorylation and immune-related gene activation and that these effects are reversed when treatment is stopped. Additionally, we found that the overexpression of double stranded RNA-containing circRNAs is able to reduce the PKR phosphorylation and the activation of immune-related pathways induced by poly(I:C). Finally, we measured the PKR phosphorylation in PBMCs isolated from multiple sclerosis patients in relapse and remission phases, but we did not obtain conclusive results since there is a very big variability between samples. In conclusion, this work reinforces the evidence on the mechanism describing the interaction between PKR and circRNA containing double-stranded structures and their role in the immune response. Besides, our experiments highlight the importance of the structure in circRNA function. Lastly, it also sheds some light into the possible implication of the circRNA-PKR axis in multiple sclerosis although further research is needed to make a better characterization of this mechanism in order to understand its potential role in the regulation of the immune response of the disease.

Dataset Information

A possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma.

Publications

A possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma.

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