Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells

Abstract

Cancer cells have the unique ability to overcome natural defense mechanisms, undergo unchecked proliferation and evade apoptosis. While chemotherapeutic drugs address this, they are plagued by a long list of side effects and have a poor success rate. This has spurred researchers to identify safer bioactive compounds that possess chemopreventive and therapeutic properties. A wide range of experimental as well as epidemiological data encourage the use of dietary agents to impede or delay different stages of cancer. In the present study, we have examined the anti-ancer property of ubiquitous phytochemical quercetin by using cell viability assay, flow cytometry, nuclear morphology, colony formation, scratch wound assay, DNA fragmentation and comet assay. Further, qPCR analysis of various genes involved in apoptosis, cell cycle regulation, metastasis and different signal transduction pathways was performed. Proteome profiler was used to quantitate the expression of several of these proteins. We find that quercetin decreases cell viability, reduces colony formation, promotes G2-M cell cycle arrest, induces DNA damage and encourages apoptosis. Quercetin induces apoptosis via activating both apoptotic pathways with a stronger effect of the extrinsic pathway relying on the combined power of TRAIL, FASL and TNF with up-regulation of caspases and pro-apoptotic genes. Quercetin could inhibit anti-apoptotic proteins by docking studies. Further, quercetin blocks PI3K, MAPK and WNT pathways. Anticancer effect of quercetin observed in cell-based assays were corroborated by molecular biology studies and yielded valuable mechanistic information. Quercetin appears to be a promising candidate with chemopreventive and chemotherapeutic potential and warrants further research.

Luteolin inhibits proliferation, triggers apoptosis and modulates Akt/mTOR and MAP kinase pathways in HeLa cells

“…The changes to nuclear morphology of HeLa cells treated with 10 and 20 µM for 48 h also justifies the assumption that apoptosis was induced by luteolin, as nuclear condensation, disintegration, nuclear blebbing and nuclear debris formation were visualized following luteolin treatment, while untreated cells did not show any significant changes in nuclear morphology. Several studies have reported that flavones, including luteolin, show similar nuclear morphological changes in several cancer cell lines, including HeLa, glioma, EC1 and KYSE450 cells ( 20 , 24 , 48 ).…”

“…Exposure of HeLa cells to 5, 10 and 20 µM luteolin for 48 h resulted in disintegration of the DNA in a ladder-like pattern, while intact DNA was observed in the untreated control. The degree of fragmentation increased in a dose-dependent manner when treated for 48 h. Flavonoids, including chrysin and quercetin, have also been demonstrated to fragment DNA in different cell lines ( 20 , 23 , 49 , 50 ). Cell cycle analysis revealed that luteolin induced sub-G1 arrest following treatment with 20 µm for 48 h, in agreement with previous studies, where arrest at the G2/M or G1 phase was observed when treated with luteolin in several different cell lines ( 14 , 22 , 24 , 27 , 43 ).…”

“…Luteolin also possesses anti-proliferative effects against A549 lung cancer cells by arresting the cell cycle at the G2 phase and initiating programmed cell death via the mitochondrial pathway, which is mediated though activation of JNK and inhibition of NF-κB ( 22 , 29 ). Luteolin suppresses the MAPK/AKT/PI3K pathway, and NF-kB and STAT3 signalling in several types of cancer cell lines, and also decreases the expression of matrix metalloproteins and β3 integrin in B16F10 and A431 melanoma cell lines, thereby inhibiting EMT ( 17 , 20 , 22 , 24 , 30 , 31 ).…”

Flavonoids Regulate Inflammation and Oxidative Stress in Cancer

“…Quercetin could inhibit anti-apoptotic proteins according to docking studies. Further, quercetin blocks PI3K, MAPK, and WNT pathways [79]. Genistein inhibited the growth of HeLa cells in a dose-dependent and time-dependent manner by modulating the expression of MMP-9 and TIMP-1 [80].…”

Genetic predisposition for cervical cancer

“…Таким образом, данный однонуклеотидный полиморфизм, локализованный в области промоторa генa FASL, приводит к подавлению активности генов, чаще всего путем блокирования транскрипции. Этот механизм в конечном итоге приводит к развитию РШМ [55]. Модуляция экспрессии генов FAS и FASL играет важную роль в контроле апоптоза и канцерогенезе [56].…”