In recent years, marine-derived functional foods with anti-tumor effects have attracted increasing attention from researchers. Protein-rich microalgae are easy to metabolize and clear in normal cells, and have lower toxicity compared with cancer cells; therefore, their anti-cancer effects cannot be ignored. Spirulina platensis is a type of microalgae with a unique green-blue color. Due to its high protein content, it is used as a dietary supplement. The main photosynthetic pigments of Spirulina are phycobiliproteins (PBP), which are divided into three types: phycoerythrin (PE), phycocyanin (PC), and allophycocyanin (APC). Phycocyanin can not only be used as a dietary nutrient, natural dye, and fluorescent label, but also as a colorant in food and cosmetics. Phycocyanin has a variety of pharmacological properties such as anti-aging, anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, and wound-healing effects. Recent studies have shown that phycocyanin exerts a certain anti-tumor effect on different types of tumor cells, such as breast cancer, lung cancer, esophageal squamous cell carcinoma, and colon cancer. Research on the anti-tumor effect of phycocyanin mainly focuses on the related pathways through which it regulates cell apoptosis, cell cycle, or cell migration. However, there are relatively few studies on the potential regulatory effect of phycocyanin on epithelial-mesenchymal transition (EMT) in the pathological mechanism of tumors.

Metastasis is a major challenge in the aggressive treatment of endometrial cancer. This is because epithelial-mesenchymal transition (EMT) is associated with a high risk of recurrence and poor prognosis; regulated by the transforming growth factor-beta (TGF-β) signaling pathway, EMT promotes tumor metastasis. Spirulina phycocyanin extract (SPE) and its purified products—allophycocyanin (APC) and C-phycocyanin (C-PC)—are nutrients with the ability to inhibit tumor growth and metastasis. This study aimed to investigate the anti-metastatic effects of SPE and its purified products (APC and C-PC) on endometrial cancer both in vitro and in vivo. First, human endometrial cancer cell lines (HEC-1A and Ishikawa) were used as in vitro models. Second, HEC-1A cells transfected with a luciferase gene were implanted into female nude mice to establish a xenograft model. The methods employed included the MTT assay, Transwell migration assay, Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and IVIS XRMS analysis. In vitro experimental results showed that SPE and its purified products (APC and C-PC) inhibited cell migration and altered the expression of EMT-related phenotypes by reversing the TGF-β/Smads signaling pathway. In vivo experimental results demonstrated that SPE suppressed the metastasis of HEC-1A-Luc cells by regulating the expression of EMT-related markers. In conclusion, SPE and its active components (APC and C-PC) reverse EMT by targeting the TGF-β/Smads signaling pathway, providing an effective therapeutic strategy for metastatic endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy worldwide. In 2022, an estimated 65,950 new cases and nearly 12,550 deaths from EC occurred in the United States [1]. Advanced-stage endometrial cancer is aggressive, with a very low 5-year survival rate of less than 30% and a high recurrence rate. Epithelial cells in the normal endometrium maintain close contact with each other via cell-cell junction proteins, whereas cells in aggressive endometrial cancer typically have irregular or absent tissue architecture. The process by which epithelial cells transform into mesenchymal cells is termed epithelial-mesenchymal transition (EMT), which promotes the formation of non-glandular colonies with mesenchymal characteristics—making them more prone to mesenchymalization, especially when exposed to transforming growth factor-beta (TGF-β). Previous studies have shown that, compared with the primary intrauterine tumor site, metastatic sites of endometrial cancer are closely associated with the upregulation of the TGF-β signaling pathway. The binding of TGF-β to TGF-β receptor II (TβRII) promotes the recruitment of TGF-β receptor I (TβRI) and the formation of a heterotetrameric complex consisting of two TβRII and two TβRI molecules. Subsequently, the active kinase domain of TβRII phosphorylates TβRI at specific sites to activate it. The canonical TGF-β/Smad pathway involves the activation of receptor-regulated Smads (R-Smads, such as Smad2 and Smad3) by TβRI; these R-Smads then form a heteromeric complex with Smad4 (common-mediator Smad). This trimeric Smad complex is subsequently translocated into the nucleus, where it cooperates with transcriptional regulators including Snail family zinc finger 1 (Snail1/SNAI1), Snail family zinc finger 2 (Snail2/SNAI2; Slug), zinc finger E-box-binding homeobox 1/2 (ZEB1/2), and twist-related protein 1/2 (Twist1/2) to regulate the expression of downstream target genes. These transcriptional regulators, also known as EMT-inducing factors, are thought to repress the transcription of epithelial marker genes (e.g., E-cadherin) and contribute to the establishment of a migratory mesenchymal phenotype. This mesenchymal phenotype is characterized by markers including N-cadherin, vimentin, alpha-smooth muscle actin (α-SMA), and fibronectin—all of which are key regulators of the prognosis of endometrial cancer.

To our knowledge, the effect of Spirulina phycocyanin extract and its active components on endometrial cancer has not been studied yet. This study aims to investigate whether Spirulina phycocyanin extract and its active components exert an anti-metastatic effect on endometrial cancer, and to clarify the underlying mechanism, with the expectation of better utilizing Spirulina phycocyanin for the treatment of various cancers.

The results of this study showed that Spirulina phycocyanin extract (SPE) and its purified components—allophycocyanin (APC) and C-phycocyanin (C-PC)—reversed TGF-β-induced migration of endometrial cancer cells and reduced peritoneal dissemination in nude mouse models by regulating the TGF-β/Smad4 signaling pathway. This mechanism involves a decrease in the expression of transcription factors such as TGF-β receptor I (TGF-βR1), Smad4, Snail, Slug, Twist1/2, and ZEB1. Subsequently, this is followed by an increase in the expression of E-cadherin and a decrease in the expression of proteins including N-cadherin, Vimentin, α-smooth muscle actin (α-SMA), fibronectin, and TMEFF2, ultimately triggering the mesenchymal-epithelial transition (MET) process. In conclusion, SPE and its purified components (APC and C-PC) may have high potential in the treatment of metastatic endometrial cancer, which will be beneficial for clinical applications.

References：Spirulina phycocyanin extract and its active components suppressepithelial-mesenchymal transition process in endometrial cancer via targeting TGF-beta1/SMAD4 signalingpathway

Keruis Biology can provide customers with highly purified allophycocyanin (APC) and C-phycocyanin (C-PC) for research and testing purposes.