Abstract
Glucocappasalin (GCP), a natural product derived from the seeds of Descurainia sophia (L.) Webb. ex Prantl, exhibits potential antitumor activity in HeLa cervical carcinoma cells. In this study, we investigated the anti-cervical cancer property of GCP through the induction of cell cycle arrest, apoptosis, and autophagy in vitro and in vivo, and elucidated the underlying molecular mechanisms. We demonstrated that treatment with GCP inhibited the growth of HeLa, Siha, and Ca Ski cell lines in a dose-dependent manner, with HeLa cells displaying particular sensitivity to the GCP treatment. Subsequently, the expression of cyclin-dependent kinase 1 (CDK1) and polo like kinase 1 (PLK1) were evaluated in HeLa cells using the CDK1 kinase assay kit, the fluorescence polarization assay, real-time quantitative PCR, and western blotting. Our results demonstrate that GCP could be employed to attenuate the expression of CDK1 and PLK1 in a dose- and time-dependent manner. The complementary results obtained by flow cytometry and western blotting allowed us to postulate that GCP may exhibit its antitumor effects by inducing G2/M cell cycle arrest. Moreover, HeLa cells treated with GCP exhibited a loss in mitochondrial membrane potential, together with the activation of caspases 3 and 9, and poly ADP-ribose polymerase (PARP). Additionally, we found that GCP could increase the formation of acidic vesicular organelles (AVOs), as well as the levels of Beclin1, LC3-II, p62, and Atg5 proteins in HeLa cells. Further studies indicated that GCP triggered autophagy via the suppression of the PI3K/AKT/mTOR signaling pathways. The autophagy inhibitor 3-methyladenine (3-MA) was used to determine whether autophagy affects the apoptosis induced by GCP. Interestingly, the inhibition of autophagy attenuated apoptosis. In vivo anti-tumor experiments indicated that GCP (60 mg/kg, i.p.) markedly reduced the growth of HeLa xenografts in nude mice without apparent toxicity. Taken together, we demonstrate that GCP induces cell cycle G2/M-phase arrest, apoptosis, and autophagy by acting on the PI3K/AKT/mTOR signaling pathways in cervical carcinoma cells. Thus, GCP may represent a promising agent in the eradication of cervical cancer.
Highlights
According to the WHO, cervical cancer is the fourth most common malignancy affecting women
The CCK8 assay was used to quantitatively measure the cell viability of the three cancer cell lines after GCP treatment (Figure 2B). These results indicate that GCP could significantly reduce the activity of cervical cancer cell lines and inhibit their cell proliferation in a dose-dependent manner, with the greatest effect of GCP being seen in HeLa cells
Previous studies have documented that three kinds of flavonoid isolated from T. kirilowii induced G2/M cell cycle arrest, apoptosis, and autophagy through the downregulation of PI3Kγ-mediated PI3K/AKT/mTOR signaling in human breast cancer cell lines (Zhang et al, 2018)
Summary
According to the WHO, cervical cancer is the fourth most common malignancy affecting women. Human papilloma virus (HPV) infection is considered as the principal etiological agent responsible for the onset of cervical carcinoma and is associated with 90% of reported cervical cancer cases (Cohen et al, 2019). Traditional strategies used in earlystage cervical carcinoma treatment, such as surgery, radiation treatment, and cytotoxic chemotherapy are widely employed. These strategies are not effective in the treatment of advanced local cervical cancer, as well as metastatic, and recurrent tumors (Wang et al, 2019). The most promising strategy for the treatment of cervical cancer should begin with the clarification of the molecular mechanisms involved in the onset and the development of cervical cancer, by revealing the critical signal transduction pathways and targeting specific molecules
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