Cancer is a leading cause of death worldwide. The burden of cancer incidence and mortality is increasing rapidly. New approaches to cancer prevention and treatment are urgently needed. Natural products are reliable and powerful sources for anticancer drug discovery. Baicalin and baicalein, two major flavones isolated from Scutellaria baicalensis Georgi, a multi-purpose traditional medicinal plant in China, exhibit anticancer activities against multiple cancers. Of note, these phytochemicals exhibit extremely low toxicity to normal cells. Besides their cytotoxic and cytostatic activities toward diverse tumor cells, recent studies demonstrated that baicalin and baicalein modulate a variety of tumor stromal cells and extracellular matrix (ECM) in the tumor microenvironment (TME), which is essential for tumorigenesis, cancer progression and metastasis. In this review, we summarize the therapeutic potential and the mechanism of action of baicalin and baicalein in the regulation of tumor microenvironmental immune cells, endothelial cells, fibroblasts, and ECM that reshape the TME and cancer signaling, leading to inhibition of tumor angiogenesis, progression, and metastasis. In addition, we discuss the biotransformation pathways of baicalin and baicalein, related therapeutic challenges and the future research directions to improve their bioavailability and clinical anticancer applications. Recent advances of baicalin and baicalein warrant their continued study as important natural ways for cancer interception and therapy.

Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

Summary: The nucleolus is a key organelle that is responsible for the synthesis of rRNA and assembly of ribosomal subunits, which is also the center of metabolic control because of the critical role of ribosomes in protein synthesis. Perturbations of rRNA biogenesis are closely related to cell senescence and tumor progression; however, the underlying molecular mechanisms are not well understood. Here, we report that cellular senescence‐inhibited gene (CSIG) knockdown up‐regulated NOLC1 by stabilizing the 5′UTR of NOLC1 mRNA, and elevated NOLC1 induced the retention of NOG1 in the nucleolus, which is responsible for rRNA processing. Besides, the expression of NOLC1 was negatively correlated with CSIG in the aged mouse tissue and replicative senescent 2BS cells, and the down‐regulation of NOLC1 could rescue CSIG knockdown‐induced 2BS senescence. Additionally, NOLC1 expression was decreased in human hepatocellular carcinoma (HCC) tissue, and the ectopic expression of NOLC1 repressed the proliferation of HCC cells and tumor growth in a HCC xenograft model.

The nucleolus is an important organelle that is responsible for the biogenesis of ribosome RNA (rRNA) and ribosomal subunits assembly. It is also deemed to be the center of metabolic control, considering the critical role of ribosomes in protein translation. Perturbations of rRNA synthesis are closely related to cell proliferation and tumor progression. Telomeric repeat-binding factor 2 (TRF2) is a member of shelterin complex that is responsible for telomere DNA protection. Interestingly, it was recently reported to localize in the nucleolus of human cells in a cell-cycle-dependent manner, while the underlying mechanism and its role on the nucleolus remained unclear. In this study, we found that nucleolar and coiled-body phosphoprotein 1 (NOLC1), a nucleolar protein that is responsible for the nucleolus construction and rRNA synthesis, interacted with TRF2 and mediated the shuttle of TRF2 between the nucleolus and nucleus. Abating the expression of NOLC1 decreased the nucleolar-resident TRF2. Besides, the nucleolar TRF2 could bind rDNA and promoted rRNA transcription. Furthermore, in hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC7721, TRF2 overexpression participated in the nucleolus stress-induced rRNA inhibition and cell-cycle arrest.

The gut microbiome is frequently dysregulated in colorectal cancer. Gut microbiota can modify bile acids (BA), which is a group of metabolites that have been linked to tumorigenesis and progression. In this study, we observed a significant deficiency in gut bacteria with bile salt hydrolase (BSH) activity in patients with liver metastatic colorectal cancer (CRLM). These patients exhibited elevated levels of conjugated primary BAs (CPBA) and decreased levels of unconjugated BAs (UBA) in their circulation. The changes in bacterial BSH activity and CPBA levels were more pronounced in male patients with CRLM. Microbial manipulation in mouse colorectal cancer models to create a BSH-deficient state increased CPBAs, reduced UBAs, and promoted liver metastasis. Specifically, taurocholic acid (TCA), a CPBA, promoted CRLM through a neutrophil-dependent mechanism. TCA upregulated TIMP1 in colorectal cancer cells, which in turn stimulated CXCL5/CXCR2-mediated neutrophil recruitment and CRLM. Alternatively, unconjugated primary and secondary BAs counteracted neutrophil migration induced by TCA in vitro and abolished TCA-promoted neutrophil recruitment and liver metastasis in vivo. Together, these findings elucidate a mechanistic role of the dysregulated gut microbiota–BA axis in CRLM, suggesting that manipulating the balance between conjugated and UBAs could be a potential therapeutic strategy to suppress colorectal cancer metastasis. Significance: In colorectal cancer, enrichment of bile salt hydrolase-deficient gut microbiota elevates conjugated primary bile acids that promote liver metastasis by inducing TIMP1-mediated neutrophil recruitment, which can be reversed by supplementing with unconjugated bile acids.