The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe²⁺ levels in vitro. Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe²⁺, is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.

Objective:To investigate the regulatory mechanism and clinical significance of RASSF5 in cutaneous melanoma.Methods:We used GEPIA and HPA online tools and TCGA and GSE53118 data sets for differential expression analysis and prognosis analysis; cBioPortal was applied to analyze the correlation between RASSF5 expression and gene mutation and methylation; "limma" R package was used to screen differential genes for GO analysis, KEGG analysis and protein-protein interaction analysis, and we also performed GSEA analysis on all genes; finally we used ESTIMATE and CIBERSORTx online tools to evaluate immune cell infiltration. The kruskal test was used to compare the differences between the groups for measurement data, the Kaplan-Meier method was used to draw the survival curve, and the Cox proportional hazard regression model was used for univariate and multivariate analysis.Results:This study found that in cutaneous melanoma, the expression level of RASSF5 was significantly lower than that of normal tissues, and the methylation level was negatively correlated. KEGG analysis and GSEA analysis showed that RASSF5 can be related to multiple signaling pathways such as immune regulation, KRAS, and P53. Further analysis showed that the expression level of RASSF5 was positively correlated with the degree of infiltration of a variety of tumor immune cells. Survival analysis found that the expression level of RASSF5 was correlated with the overall survival rate of patients with cutaneous melanoma, and multivariate regression analysis found that RASSF5 was an independent predictor of cutaneous melanoma. Finally, using the GSE53118 dataset to verify again, RASSF5 is related to the overall survival rate of patients with cutaneous melanoma and can be used as an independent predictor.Conclusions:RASSF5 may regulate the occurrence and development of cutaneous melanoma cells through a variety of ways. It is a potential biological prognostic marker and therapeutic target.

Objective:To investigate the regulatory mechanism and clinical significance of RASSF5 in cutaneous melanoma.Methods:We used GEPIA and HPA online tools and TCGA and GSE53118 data sets for differential expression analysis and prognosis analysis; cBioPortal was applied to analyze the correlation between RASSF5 expression and gene mutation and methylation; "limma" R package was used to screen differential genes for GO analysis, KEGG analysis and protein-protein interaction analysis, and we also performed GSEA analysis on all genes; finally we used ESTIMATE and CIBERSORTx online tools to evaluate immune cell infiltration. The kruskal test was used to compare the differences between the groups for measurement data, the Kaplan-Meier method was used to draw the survival curve, and the Cox proportional hazard regression model was used for univariate and multivariate analysis.Results:This study found that in cutaneous melanoma, the expression level of RASSF5 was significantly lower than that of normal tissues, and the methylation level was negatively correlated. KEGG analysis and GSEA analysis showed that RASSF5 can be related to multiple signaling pathways such as immune regulation, KRAS, and P53. Further analysis showed that the expression level of RASSF5 was positively correlated with the degree of infiltration of a variety of tumor immune cells. Survival analysis found that the expression level of RASSF5 was correlated with the overall survival rate of patients with cutaneous melanoma, and multivariate regression analysis found that RASSF5 was an independent predictor of cutaneous melanoma. Finally, using the GSE53118 dataset to verify again, RASSF5 is related to the overall survival rate of patients with cutaneous melanoma and can be used as an independent predictor.Conclusions:RASSF5 may regulate the occurrence and development of cutaneous melanoma cells through a variety of ways. It is a potential biological prognostic marker and therapeutic target.

It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-B (NF-B) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy.