Abstract
Marine sponges are known to produce numerous bioactive secondary metabolites as defense strategies to avoid predation. Manzamine A is a sponge-derived β-carboline-fused pentacyclic alkaloid with various bioactivities, including recently reported anticancer activity on pancreatic cancer. However, its cytotoxicity and mode of action against other tumors remain unclear. In this study, we exhibit that manzamine A reduced cell proliferation in several colorectal cancer (CRC) cell lines. To further investigate the manzamine A triggered molecular regulation, we analyzed the gene expression with microarray and revealed that pathways including cell cycle, DNA repair, mRNA metabolism, and apoptosis were dysregulated. We verified that manzamine A induced cell cycle arrest at G0/G1 phase via inhibition of cyclin-dependent kinases by p53/p21/p27 and triggered a caspase-dependent apoptotic cell death through mitochondrial membrane potential depletion. Additionally, we performed bioinformatics analysis and demonstrated that manzamine A abolished epithelial–mesenchymal transition process. Several mesenchymal transcriptional factors, such as Snail, Slug, and Twist were suppressed and epithelial marker E-cadherin was induced simultaneously in HCT116 cells by manzamine A, leading to the epithelial-like phenotype and suppression of migration. These findings suggest that manzamine A may serve as a starting point for the development of an anticancer drug for the treatment of metastatic CRC.
Highlights
Colorectal cancer (CRC) is the third-most common cancer in both genders and the fourth leading cause of cancer related mortality, responsible for 9.7% of cancer-related deaths worldwide [1,2,3].Distant metastasis caused by disease recurrence and development of drug resistance is the mainMar
We showed that Manzamine A (Manz A) significantly inhibited the proliferation of several colorectal cancer (CRC) cell lines
We found that Manz A significantly decreased the cell viability of all colorectal carcinoma cells and showed a higher efficacy on HCT116 compared with HT-29 and DLD-1 (Figure 1A)
Summary
Colorectal cancer (CRC) is the third-most common cancer in both genders and the fourth leading cause of cancer related mortality, responsible for 9.7% of cancer-related deaths worldwide [1,2,3].Distant metastasis caused by disease recurrence and development of drug resistance is the mainMar. The most frequent aberrations found in CRC patients are mutations in adenomatous polyposis coli (APC), catenin-β1 (CTNNB1), family with sequence similarity 123B (FAM123B; known as AMER1), kirsten rat sarcoma viral oncogene homolog (KRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), erb-b2 receptor tyrosine kinase 2 E (RBB2), SMAD family member 4 (SMAD4), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-α (PIK3CA), transforming growth factor-β receptor 2 (TGFBR2), AT-rich interactive domain 1A (ARID1A), and tumor Protein P53 (TP53) These mutations promote tumorigenesis by perturbing the key signaling pathways, such as WNT–β-catenin, epidermal growth factor (EGF)–mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)–AKT, and TGFβ signaling pathways, or affecting genes that regulate fundamental processes, such as DNA repair, cell cycle progression and proliferation [2,9]
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