Mushrooms are valued for their nutritional qualities and have been used in traditional medicine since the Neolithic era. They exhibit various bioactivities, including antioxidant, hypocholesterolemic, immunomodulatory, and anticancer effects. The anticancer effects arise via direct action on tumor cells and indirect modulation of the immune system; the latter is the predominant mechanism. Numerous studies indicate that various mushroom species are potent immunostimulants because their cell wall polysaccharides and proteoglycans are recognized by intestinal immune cells. This enhances antitumor immunity through multiple molecular pathways. However, their direct effects on cancer cells are of questionable physiological relevance due to bioavailability constraints. Nevertheless, we hypothesize that the accumulation of non-absorbed polysaccharides in the gastrointestinal tract positions mushrooms as dual-action agents with the potential to treat colorectal cancer by providing indirect immunomodulation and direct local tumor suppression. Conversely, the direct anticancer effects of mushrooms are generally attributed to bioactive secondary metabolites that influence essential cellular processes, including signaling pathways, cell cycle regulation, apoptosis, autophagy, cellular migration, invasion, and cancer stem cell characteristics. Beyond these anticancer effects, clinical evidence suggests that certain mushroom-derived substances can improve survival outcomes for cancer patients and provide supportive care benefits in oncology, thereby improving quality of life. Specifically, mushrooms may mitigate the side effects of chemotherapy and radiotherapy, bolster immune function often suppressed by cancer treatments, and enhance overall well-being. In this review, we discuss the therapeutic benefits of dietary and medicinal mushrooms in cancer care, as well as unresolved challenges and future research directions.

In normal tissue, cellular homeostasis is largely driven by two catabolic pathways: apoptosis and autophagy. Apoptosis, or programmed cell death, is regulated by pro-apoptotic factors, and promotes the removal of problematic cells. Autophagy, which in turn includes three forms: macro-, micro-, and chaperone-mediated autophagy, can promote both cell survival by selectively removing potentially apoptosis-inducing factors and raising the threshold of stress required for the induction of cell death. Recently, evidence has been accumulating suggesting the existence of common molecular pathways between autophagy and apoptosis, as well as the influence of the extracellular matrix on these processes. One of the important enzymes involved in the coordination and regulation of these processes is transglutaminase 2 (TG2). Different types of TG2 activities are involved in maintaining the dynamic balance between extracellular matrix and intracellular autophagy/apoptosis processes, while dysregulation of these processes may contribute to the pathogenesis of various human diseases, including oncogenesis. For example, TG2 can promote the degradation of pro-apoptotic proteins and the survival of renal cell carcinoma cells under nutrient-deficient conditions by modulating the autophagy process. In cells of various tissues deprived of TG2, aggregates of ubiquitinated proteins and damaged mitochondria are observed, which in turn induces proteotoxic stress and cell death. conversely, the transamidase activity of TG2 was observed to inhibit anti-apoptotic signaling in a human leukemic monocytic lymphoma model. In the present review, a number of important functions of TG2 in oncogenesis are described, along with the dual role of TG2 in modulating such opposite processes as cell survival and cell death.

The survival of disseminating tumor cells at the invasive edge and in metastatic foci depends on their ability to counteract anti-tumor immunity. The epithelial–mesenchymal transition (EMT) process is associated with the recruitment of immune-suppressive myeloid cells. The onset of the EMT gene expression program is controlled by several transcriptional master-regulators, including ZEB1. Using engineered breast cancer cell lines with different statuses of ZEB1, we examined the effects of ZEB1 on the expression of different pro-inflammatory cytokines. Our results suggest that ZEB1 plays an important role in regulating the expression of CCL2 (C-C motif ligand 2, a.k.a. MCP-1), the main chemoattractant of monocytes. Forced expression of ZEB1 in epithelial MCF-7 cells significantly increased the expression level of CCL2, which was further enhanced by TNF-α. On the contrary, knock-out of ZEB1 in pseudo-mesenchymal MDA-MB-231 cells led to a complete loss of CCL2 expression. Moreover, this effect was not restored by TNF-α induction. Also, positive ZEB1 status in breast cancer cells promoted the chemoattraction of THP-1 macrophages in co-culture experiments. Analysis of publicly available ChIP-seq data implicated ZEB1 in the regulation of CCL2 gene transcription. Taken together, these data suggest that ZEB1 is involved in the formation of the EMT-associated pro-tumor immune microenvironment.

Background/Objectives: Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers and is a leading cause of cancer-related deaths worldwide. Pharmacological targeting of the p53–MDM2 interaction to activate wild-type p53 is a promising strategy for treating NSCLC that retain functional p53 (approximately 50% of all cases). Methods: We screened 33 ethnomedicinal Vietnamese plant extracts for their anticancer effects using p53-expressing and p53-null NSCLC cell models, as well as two non-cancerous cell lines for control. We used an array of different experimental approaches including NMR spectroscopy; molecular docking; an MTT test; cell cycle analysis; apoptosis analysis; wound healing, migration, and invasion assays; Real-Time PCR; immunoblotting; and Seahorse energy profiling to characterize and study the effects of these bioactive compounds on NSCLC cells. Results: Ethanol extract of Zanthoxylum nitidum stems and twigs demonstrated potent and selective activity by inducing p53-dependent cell cycle arrest and apoptosis. Phytochemical analysis identified several benzophenanthridine alkaloids as active constituents. Molecular docking revealed their strong in silico binding to MDM2. Notably, nitidine was the most promising compound among the molecules tested. Unlike nutlin, but similar to SP141 (two well-known MDM2 inhibitors), nitidine strongly stabilized p53 while concomitantly attenuating MDM2 at the protein level. Surprisingly, this effect was p53-independent. Additionally, nitidine suppressed the EMT master regulator Snail, and hence disrupted cellular bioenergetics and inhibited migration and invasion of NSCLC cells. Conclusions: Our findings identify Z. nitidum and nitidine as promising sources for developing novel MDM2-targeting therapeutics against NSCLC irrespective of the p53 status.