Ethanol Extract of Citrus grandis ‘Tomentosa’ Exerts Anticancer Effects by Targeting Skp2/p27 Pathway in Non‐Small Cell Lung Cancer

Abstract

ScopeThis study aims to investigate the anticancer properties of Citrus grandis ‘Tomentosa’ (CGT) in non‐small cell lung cancer (NSCLC).Methods and resultsThe ethanol extract of CGT (CGTE) is prepared by using anhydrous ethanol and analyzed by ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS), revealing that the main chemical components in CGTE are flavonoids and coumarins, such as naringin, rhoifolin, apigenin, bergaptol, and osthole. CGTE at concentrations without inducing cell death significantly inhibits cell proliferation via inducing cell cycle G1 phase arrest by MTT, colony formation, and flow cytometry assays, implying that CGT has anticancer potential. CGTE markedly inhibits the activity of Skp2‐SCF E3 ubiquitin ligase, decreases the protein level of Skp2, and promotes the accumulation of p27 by co‐immunoprecipitation (co‐IP) and in vivo ubiquitination assay; whereas Skp2 overexpression rescues the effects of CGTE in NSCLC cells. In subcutaneous LLC allograft and A549 xenograft mouse models, CGTE, without causing obvious side effects in mice, significantly inhibits lung tumor growth by targeting the Skp2/p27 signaling pathway.ConclusionThese findings demonstrate that CGTE efficiently inhibits NSCLC proliferation both in vitro and in vivo by targeting the Skp2/p27 signaling pathway, suggesting that CGTE may serve as a therapeutic candidate for NSCLC treatment.

Bergaptol, a Major Furocoumarin in Citrus: Pharmacological Properties and Toxicity

“…Moreover, bergaptol could inhibit the activity of decrease the level of Skp2 protein, leading to reduced pro stabilization of cyclin-dependent kinase inhibitor p27, [52,53]. This potential is supported by the study of eth grandis Tomentosa) in A549 human lung carcinoma cells [52]. These results also suggest that bergaptol may influe pathways contributing to the inhibition of cell prolifera cycle arrest.…”

“…It has been shown to induce cell expression of pro-apoptotic protein Bax and decreasing totic protein Bcl-2 expression in a dose-dependent relat the transcription rate of Bax/Bcl-2 results in cytochrom cytosol and consequently activation of caspase-9 an caspase-3 not only induces apoptosis but also causes ce division cycle 6 (CDC6), an essential regulator of DN [49,51]. Moreover, bergaptol could inhibit the activity of decrease the level of Skp2 protein, leading to reduced pro stabilization of cyclin-dependent kinase inhibitor p27, [52,53]. This potential is supported by the study of eth grandis Tomentosa) in A549 human lung carcinoma cells [52].…”

“…The activated caspase-3 not only induces apoptosis but also causes cell cycle arrest by cleavage of cell division cycle 6 (CDC6), an essential regulator of DNA replication at the G1/S phase [49,51]. Moreover, bergaptol could inhibit the activity of Skp2-SCF E3 ubiquitin ligase and decrease the level of Skp2 protein, leading to reduced protein degradation and consequent stabilization of cyclin-dependent kinase inhibitor p27, a key regulator of the cell cycle [52,53]. This potential is supported by the study of ethanolic extract of pomelo (Citrus grandis Tomentosa) in A549 human lung carcinoma cells and an LLC tumor mouse model [52].…”

“…Moreover, bergaptol could inhibit the activity of Skp2-SCF E3 ubiquitin ligase and decrease the level of Skp2 protein, leading to reduced protein degradation and consequent stabilization of cyclin-dependent kinase inhibitor p27, a key regulator of the cell cycle [52,53]. This potential is supported by the study of ethanolic extract of pomelo (Citrus grandis Tomentosa) in A549 human lung carcinoma cells and an LLC tumor mouse model [52]. These results also suggest that bergaptol may influence changes in various molecular pathways contributing to the inhibition of cell proliferation by promoting G1 phase cell cycle arrest.…”

The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

“…Mechanistically, TRAF6 ubiquitinates the K63 site of p53 to limit its mitochondrial translocation of p53, contributing to tumor development and drug resistance (Zhang et al 2016 ). Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) promoted the polyubiquitination of solute carrier family 7 member 11 (SLC7A11) to trigger the degradation of SLC7A11, thereby promoting ferroptosis of CRC (Huang et al 2023a , b ). Interestingly, all the E3s described above are RING-type E3s; however, additional studies are needed to further elucidate other E3s in the chemotherapeutic mechanism of colon cancer (CC).…”