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Cucurbitacin C (CuC), a novel analogue of triterpenoids cucurbitacins, confers a bitter taste in cucumber. Genes and signaling pathways responsive for biosynthesis of CuC have been identified in the recent years. In the present study, we explored the anti-cancer effects of CuC against human cancers in vitro and in vivo. CuC inhibited proliferation and clonogenic potential of multiple cancer cells in a dose-dependent manner. Lowdose CuC treatment induced cell cycle arrest at G1 or G2/M stage in different cancer lines, whereas high-dose treatment of CuC caused apoptosis in cancer cells. PI3KAkt signaling pathway was found to be one of the major pathways involved in CuC-induced cell growth arrest and apoptosis by RNA-Seq and Western blotting. Mechanistic dissection further confirmed that CuC effectively inhibited the Akt signaling by inhibition of Akt phosphorylation at Ser473. In vivo CuC treatment (0.1 mg/kg body weight) effectively inhibited growth of cancer cell-derived xenograft tumors in athymic nude mice and caused significant apoptosis. Our findings for the first time demonstrated the potential therapeutic significance of CuC against human cancers. [ABSTRACT FROM AUTHOR]

Abstract Colon cancer (CC) is a prevalent malignant tumor of the gastrointestinal tract and ranks among the leading causes of death in cancer patients worldwide. Cucurbitacin, a group of tetracyclic triterpenoids widely found in Cucurbitaceae plants, exhibits diverse pharmacological activities. However, the pharmacological activity of cucurbitacin C (CuC), a cucurbitacin derivative exclusively present in cucumbers, remains unclear. To investigate CuC's action targets and potential targets for CC, we utilized a database to obtain relevant information. Additionally, we identified differentially expressed genes in CC patients from The Cancer Genome Atlas and discovered 64 crossover targets formed through the intersection of drug‐disease targets. Through the construction of a protein‐protein interaction network, we identified 20 central genes. Enrichment analysis revealed that the cross‐targets were significantly enriched in four signaling pathways, namely, the PI3K‐Akt, Ras, MAPK, and IL‐17 signaling pathways. Correlation and expression analysis of the enriched central genes led to the identification of 7 key targets, among which matrix metalloproteinases (MMP)‐1, MMP‐3, and MMP‐13 demonstrated a significant association with poor prognosis in patients. Furthermore, we validated the network pharmacology results with in vitro and in vivo experiments. CuC can effectively inhibit the proliferation and migration of HCT‐116. CuC also can suppress the colon tumor growth in vivo, while reducing the expression of placental growth factor, MMP‐1, MMP‐3, MMP‐9, and MMP‐13 both in vitro and in vivo, consistent with the predicted results. Together, our results demonstrated that CuC holds promise as a potential agent for CC treatment.

Background: Cholangiocarcinoma (CCA) is a malignant epithelial tumor characterized by a dismal prognosis. Given the lack of therapeutic strategies and durable treatment options currently available, identifying innovative treatments for CCA is an urgent unmet clinical need. Cucurbitacin C (CuC) is a distinct variant of the cucurbitacin family, displaying promising anti-cancer activity against various tumor types. The primary objective of our research is to elucidate the promising effects of CuC on CCA. Methods: The impact of CuC on CCA cell lines was assessed by cell count kit-8 assay, EdU staining assay, colony formation assay, wound-healing assay, and Transwell assay. Flow cytometric analysis was conducted to explore the function of CuC treatments on cell-cycle distribution and apoptosis in CCA cells. Computational biology and network pharmacology approaches were utilized to predict potential targets of CuC. Furthermore, a tumor xenograft mouse model was established using CCA cells to explore the anti-cancer effects of CuC in vivo. Results: Our research findings revealed that CuC exerted a suppressive effect on CCA cell progression. Cell viability assays, EdU staining assays, and colony formation assays demonstrated that CuC effectively suppressed viability and proliferation of CCA cells. Wound-healing assays and Transwell assays indicated that CuC effectively inhibits the migratory and invasive capabilities of CCA cells. Flow cytometry analysis elucidated that CuC played its anti-proliferative role in CCA cells by arresting G0/G1 phase and increasing apoptosis. Through bioinformatics and network pharmacology analysis, in conjunction with western blot analysis, we demonstrated CuC mediated the inhibition of CCA cell progression through modulation of JAK2/STAT3 pathway. Additionally, the CCA xenograft tumor model was established, and the results supported the inhibition of CuC treatment against CCA progression in vivo. Conclusion: Our study demonstrates that CuC possesses notable capabilities to suppress cell proliferation, migration, and invasion in CCA. Importantly, the inhibitory effects of CuC on CCA progression are attributed to its modulation of the JAK2/STAT3 signaling pathway. Altogether, our study demonstrated that CuC holds promise as a prospective therapeutic agent for treating CCA. [ABSTRACT FROM AUTHOR]

Cucurbitacins are seldom found in pickling cucumber, but when present, make finished products unpalatable. Liquid chromatography-time-of-flight mass spectrometry was employed to determine cucurbitacins in 'Hanzil' (bitter) and 'Vlaspik' (non-bitter) pickling cucumbers subjected to acidification or fermentation. Cucurbitacins C (CuC) and C-glycoside were putatively identified in 'Hanzil' cucumber fruits while undetectable in 'Vlaspik'. The major cucurbitacin in 'Hanzil', CuC, increased in concentration with cucumber size, ranging from 28 ppm in size 2A to >74 ppm in size 4+ fruits. Endocarp had the highest CuC concentration (88.7 ± 44.3 ppm) followed by mesocarp (30.6 ± 15.1 ppm) and exocarp (2.58 ± 1.75 ppm). CuC was 3-fold lower in acidified cucumber (15.7 ± 10.3 ppm) and 10-fold less in fermented cucumber (4.90 ± 3.94 ppm) than when fresh (47.9 ± 22.8 ppm). Fermentation has potential for de-bittering of cucurbits, and oversized bitter cucumbers could serve as a source of CuC for exploration of bioactivities. • LC-TOF-MS was used to detect and quantify cucurbitacins in cucumber. • Cucurbitacin C content increased with increasing cucumber size. • Bitter cucumber endocarp tissue contained the most cucurbitacin C. • Cucurbitacin C was significantly decreased after fermentation. • Fermentation has potential as a de-bittering method for the pickle industry. [ABSTRACT FROM AUTHOR]

Cucurbitacin C (CuC), a novel analogue of triterpenoids cucurbitacins, confers a bitter taste in cucumber. Genes and signaling pathways responsive for biosynthesis of CuC have been identified in the recent years. In the present study, we explored the anti-cancer effects of CuC against human cancers in vitro and in vivo. CuC inhibited proliferation and clonogenic potential of multiple cancer cells in a dose-dependent manner. Low-dose CuC treatment induced cell cycle arrest at G1 or G2/M stage in different cancer lines, whereas high-dose treatment of CuC caused apoptosis in cancer cells. PI3K-Akt signaling pathway was found to be one of the major pathways involved in CuC-induced cell growth arrest and apoptosis by RNA-Seq and Western blotting. Mechanistic dissection further confirmed that CuC effectively inhibited the Akt signaling by inhibition of Akt phosphorylation at Ser473. In vivo CuC treatment (0.1 mg/kg body weight) effectively inhibited growth of cancer cell-derived xenograft tumors in athymic nude mice and caused significant apoptosis. Our findings for the first time demonstrated the potential therapeutic significance of CuC against human cancers.

Cucurbitacin C (CuC), a novel analogue of triterpenoids cucurbitacins, confers a bitter taste in cucumber. Genes and signaling pathways responsive for biosynthesis of CuC have been identified in the recent years. In the present study, we explored the anti-cancer effects of CuC against human cancers in vitro and in vivo. CuC inhibited proliferation and clonogenic potential of multiple cancer cells in a dose-dependent manner. Low-dose CuC treatment induced cell cycle arrest at G1 or G2/M stage in different cancer lines, whereas high-dose treatment of CuC caused apoptosis in cancer cells. PI3K-Akt signaling pathway was found to be one of the major pathways involved in CuC-induced cell growth arrest and apoptosis by RNA-Seq and Western blotting. Mechanistic dissection further confirmed that CuC effectively inhibited the Akt signaling by inhibition of Akt phosphorylation at Ser473. In vivo CuC treatment (0.1 mg/kg body weight) effectively inhibited growth of cancer cell-derived xenograft tumors in athymic nude mice and caused significant apoptosis. Our findings for the first time demonstrated the potential therapeutic significance of CuC against human cancers. [ABSTRACT FROM AUTHOR]

Key message: In this study, we first linked the signal molecule H2S with cucurbitacin C, which can cause the bitter taste of cucumber leaves and fruit, and specifically discuss its molecular mechanism. Cucurbitacin C (CuC), a triterpenoid secondary metabolite, enhances the resistance of cucumber plants to pathogenic bacteria and insect herbivores, but results in bitter-tasting fruits. CuC can be induced in some varieties of cucumber on exposure to plant stressors. The gasotransmitter hydrogen sulfide (H2S) participates in multiple physiological processes relating to plant stress resistance. This study focused on the effect of H2S on low temperature-induced CuC synthesis in cucumber. The results showed that treatment of cucumber leaves at 4 °C for 12 h enhanced the content and production rate of H2S and increased the expression of genes encoding enzymes involved in H2S generation, Csa2G034800.1 (CsaLCD), Csa1G574800.1 (CsaDES1), and Csa1G574810.1 (CsaDES2). In addition, treatment at 4 °C or with exogenous H2S upregulated the expression of CuC synthetase-encoding genes and the resulting CuC content in cucumber leaves, whereas pretreatment with hypotaurine (HT, a H2S scavenger) before treatment at 4 °C offset these effects. In vitro, H2S could increase the S-sulfhydration level of His-Csa5G156220 and His-Csa5G157230 (both bHLH transcription factors), as well as their binding activity to the promoter of Csa6G088690, which encodes the key synthetase for CuC generation. H2S pretreatment enhanced the cucumber leaves resistance to the Phytophthora melonis. Together, these results demonstrated that H2S acts as a positive regulator of CuC synthesis as a result of the modification of proteins by S-sulfhydration, also providing indirect evidence for the role of H2S in improving the resistance of plants to abiotic stresses and biotic stresses by regulating the synthesis of secondary metabolites. [ABSTRACT FROM AUTHOR]

Cucurbitacin C, a bitter substance in Cucumis sativus L., was isolated from green leaves by using phytochemical methods. An analytical method using high-performance liquid chromatography (HPLC) was established for the quantification of cucurbitacin C in different parts of the cucumber plant at different growth periods. Cucurbitacin C was detected in the leaves and stems but not in the female flowers, fruits, roots and leafstalks. The level of cucurbitacin C decreased significantly with the process of young leaves turning old. A new compound named 23,24-dihydrocucurbitacin C, regarded as the next metabolite of cucurbitacin C, was determined unambiguously by HPLC-quadrupole-time-of-flight mass spectrometry and nuclear magnetic resonance. [ABSTRACT FROM AUTHOR]

Agricultural management has profound effects on soil communities. Activities such as fertilizer inputs can modify the composition of arbuscular mycorrhizal fungi (AMF) communities, which form important symbioses with the roots of most crop plants. Intensive conventional agricultural management may select for less mutualistic AMF with reduced benefits to host plants compared to organic management, but these differences are poorly understood. AMF are generally evaluated based on their direct growth effects on plants. However, mycorrhizal colonization also may alter plant traits such as tissue nutrients, defensive chemistry, or floral traits, which mediate important plant-insect interactions like herbivory and pollination. To determine the effect of AMF from different farming practices on plant performance and traits that putatively mediate species interactions, we performed a greenhouse study by inoculating Cucumis sativus (cucumber, Cucurbitaceae) with AMF from conventional farms, organic farms, and a commercial AMF inoculum. We measured growth and a suite of plant traits hypothesized to be important predictors of herbivore resistance and pollinator attraction. Several leaf and root traits and flower production were significantly affected by AMF inoculum. Both conventional and organic AMF reduced leaf P content but increased Na content compared to control and commercial AMF. Leaf defenses were unaffected by AMF treatments, but conventional AMF increased root cucurbitacin C, the primary defensive chemical of C. sativus, compared to organic AMF. These effects may have important consequences for herbivore preference and population dynamics. AMF from both organic and conventional farms decreased flower production relative to commercial and control treatments, which may reduce pollinator attraction and plant reproduction. AMF from both farm types also reduced seed germination, but effects on plant growth were limited. Our results suggest that studies only considering AMF effects on growth may overlook changes in plant traits that have the potential to influence interactions, and hence yield, on farms. Given the effects of AMF on plant traits documented here, and the great importance of both herbivores and pollinators to wild and cultivated plants, we advocate for comprehensive assessments of mycorrhizal effects in complex community contexts, with the aim of incorporating multispecies interactions both above and below the soil surface. [ABSTRACT FROM AUTHOR]