Regulation Of Cancer Cell Death Research Articles

Comprehensive analysis of multiple regulated cell death risk signatures in lung adenocarcinoma

BackgroundRegulated cell death (RCD) has considerable impact on tumor progress and sensitivity of treatment. Lung adenocarcinoma (LUAD) show a high resistance for conventional radiotherapies and chemotherapies. Currently, regulation of cancer cell death has been emerging as a new promising therapeutic avenue for LUAD patients. However, the crosstalk in each pattern RCD is unclear. MethodsWe integrated collected the hub-genes of 12 RCD subroutines and compressively analyzed these hub-genes synergistic effect in LUAD. The characters of RCD genes expression and prognosis were developed in The Cancer Genome Atlas (TCGA)-LUAD data. We developed and validated an RCD risk model based on TCGA and GSE70294 data set, respectively. Functional annotation and tumor immunotherapy based on the risk model were also investigated. Results28 RCD-related genes and two LUAD molecular cluster were identified. Survival analysis revealed that the prognosis in high-risk group was worser than those in low-risk group. Functional enrichment analysis indicated that the RCD risk model correlated with immune responses. Further analysis indicated that the high-risk group in RCD risk model exhibited an immunosuppressive microenvironment and a lowly immunotherapy responder ratio. ConclusionsWe present an RCD risk model which have a promising ability in predicting LUAD prognosis and immunotherapy response.

Abstract A055: Context-dependent role of acid sphingomyelinase in pancreatic ductal adenocarcinoma

Abstract Sphingolipids, a class of lipids that includes the bioactive molecules ceramide and sphingosine-1-phosphate (S1P), play a contrasting role in the regulation of cancer cell death and survival. Acid sphingomyelinase (SMPD1) is the key enzyme that breaks down sphingomyelin into ceramide, accounting for more than 50% of the cellular ceramide supply and influencing the development of cancer. Here, we studied the role of SMPD1 in different cellular compartments during pancreatic ductal adenocarcinoma (PDAC) carcinogenesis. We performed a targeted quantitative plasma metabolite analysis of 637 patients (PDAC, 356; nonpancreatic disease, 281). We completed the IHC multiplex staining in the TMA of 124 patients with PDAC. Using CRISPR-Cas9 gene editing, SMPD1 was deleted in PDAC cell lines. The influence of SMPD1-KO on proliferation, colony formation, and migration was studied. Tumor progression and carcinogenesis was monitored in an orthotopic PDAC model and metastasis models using SMPD1 null cells, as well as in KC and KPC mice. Plasma metabolite analysis of 637 patients (PDAC, 356; nonpancreatic disease, 281) revealed the most pronounced changes in the group of complex lipids with the highest prevalence of sphingomyelins and ceramides. Overall survival was significantly correlated with high SMPD1 expression in tumor tissue in two independent cohorts. Interestingly, IHC multiplex analysis of SMPD1 'high expression' in cancer cells was associated with poorer survival, while SMPD1 'high expression' in immune cells was associated with longer overall survival. Expression level of Smpd1 differed from preneoplastic to neoplastic lesions in PDAC mouse tissue. Smpd1-KO in PDAC cell lines resulted in decreased proliferation, colony formation, and migration. In an orthotopic mouse model, Smpd1-KO clones resulted in significantly lower tumor weight and size compared to WT clones. Furthermore, the injection of WT clones into global Smpd1het-KO mice resulted in a significant increase in tumor weight compared to the injection of WT clones into WT mice. In two different metastasis models, injecting Smpd1-KO led to a significantly reduced formation of metastases in the lung and liver compared to WT clones. Interestingly, injecting WT clones into global Smpd1het-KO mice resulted in a significant decrease in metastasis formation in the lung compared to the injection of WT clones into WT mice. In general, we show a significant increase in survival in an orthotopic PDAC model using PDAC Smpd1-KO cells. In conclusion, SMPD1 has a context-dependent role in cancer cells and immune cells in PDAC. Inhibition of SMPD1 specifically in cancer cells is a viable therapeutic option, which should be explored in future studies. Citation Format: Ahmed Alnatsha, Qi Li, Klea Ricku, Prince Allawadhi, Jianying Xu, Didem Saka, Theresa Weltermann, Quan Zhaou, Nicole Schreiner, Kirsten Lauber, Ivonne Regel, Ujjwal Mukund Mahajan, Julia Mayerle. Context-dependent role of acid sphingomyelinase in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A055.

Arresting the G2/M phase empowers synergy in magnetic nanomanipulator-based cancer mechanotherapy and chemotherapy

Using mechanical cues for cancer cells can realize precise control and efficient therapeutic effects. However, the cell cycle-specific response for dynamic mechanical manipulation is barely investigated. Here, RGD-modified iron oxide nanomanipulators were utilized as the intracellular magneto-mechanical transducers to investigate the mechanical impacts on the cell cycle under a dynamic magnetic field for cancer treatment. The G2/M phase was identified to be sensitive to the intracellular magneto-mechanical modulation with a synergistic treatment effect between the pretreatment of cell cycle-specific drugs and the magneto-mechanical destruction, and thus could be an important mechanical-targeted phase for regulation of cancer cell death. Finally, combining the cell cycle-specific drugs with magneto-mechanical manipulation could significantly inhibit glioma and breast cancer growth in vivo. This intracellular mechanical stimulus showed cell cycle-dependent cytotoxicity and could be developed as a spatiotemporal therapeutic modality in combination with chemotherapy drugs for treating deep-seated tumors.

Epigenetic Effects of Essential Fatty Acids

In this review, the recent knowledge regarding the epigenetic effects of the four most important dietary fatty acids will be discussed. Besides as important sources of fuel for sustaining life, fatty acids are important biomolecules/precursors involved in diverse cellular activities. Insufficient amount of fatty acids present in the body, especially for those essential polyunsaturated fatty acids (PUFAs) which cannot be synthesized (alpha-linolenic acid and linoleic acid)/are inefficiently synthesized (eicosapentaenoic acid and docosahexaenoic acid) by the body, could lead to various human diseases and developmental abnormities. The biological roles of these four essential PUFAs have been extensively studied and reviewed throughout the last decades, e.g., biosynthesis of long-chain PUFAs and eicosanoids, anti-inflammation, cardiovascular protection, inhibition of cancer cell proliferation, anti-metastasis, anti-angiogenesis, and regulation of cancer cell death; interestingly, it has been shown more recently that some of the above attributes could be explained by virtue of PUFAs’ influence on gene activities involving DNA methylation/demethylation, histone modifications, and non-coding RNA expression. Essential PUFAs are important biomolecules that mediate epigenetic control of gene expressions; therefore, understanding more about the epigenetic effects associated with these dietary fatty acids are crucial to finding ways for improving human health.

Regulation of cancer cell death by a novel compound, C604, in a c-Myc-overexpressing cellular environment

The proto-oncogene c-Myc has been implicated in a variety of cellular processes, such as proliferation, differentiation and apoptosis. Several c-Myc targets have been studied; however, selective regulation of c-Myc is not easy in cancer cells. Herein, we attempt to identify chemical compounds that induce cell death in c-Myc-overexpressing cells (STF-cMyc and STF-Control) by conducting MTS assays on approximately 4000 chemical compounds. One compound, C604, induced cell death in STF-cMyc cells but not STF-Control cells. Apoptotic proteins, including caspase-3 and poly(ADP-ribose) polymerase (PARP), were cleaved in C604-treated STF-cMyc cells. In addition, SW620, HCT116 and NCI-H23 cells, which exhibit higher basal levels of c-Myc, underwent apoptotic cell death in response to C604, suggesting a role for C604 as an inducer of apoptosis in cancer cells with c-Myc amplification. C604 induced cell cycle arrest at the G2/M phase in cells, which was not affected by apoptotic inhibitors. Interestingly, C604 induced accumulation of c-Myc and Cdc25A proteins. In summary, a chemical compound was identified that may induce cell death in cancer cells with c-Myc amplification specifically through an apoptotic pathway.

RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients

BackgroundA major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients.MethodsHCT-116 colon cancer cells were treated with CPT, OXP, and IL-6 separately or in combination in a time and dose-dependent manner and examined for phosphorylated and non-phosphorylated RKIP and STAT3 via Western blot analysis. STAT3 transcriptional activity was measured via a luciferase reporter assay in HCT116 cells treated with CPT, IL-6 or transfected with JAK 1, 2 separately or in combination. We extended these observations and determined STAT3 and RKIP/ pRKIP in tumor microarrays (TMA) in stage II colon cancer patients.ResultsWe demonstrate IL-6-mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro in human colon cancer cells. OXP and CPT block IL-6 mediated STAT3 activation and RKIP phosphorylation via the inhibition of the interaction of STAT3 with gp130. We determined that STAT3 and nuclear pRKIP are significantly associated with poor patient prognosis in stage II colon cancer patients.ConclusionsIn the analysis of tumor samples from stage II colon cancer patients and the human colon carcinoma cell line HCT116, pRKIP and STAT3, 2 proteins potentially involved in the resistance to conventional treatments were detected. The phosphorylation of pRKIP and STAT3 are induced by the cytokine IL-6 and suppressed by the chemotherapeutic drugs CPT and OXP. Therefore, these results suggest that STAT3 and pRKIP may serve as prognostic biomarkers in stage II colon cancer patients and may improve chemotherapy.