Chamomile Essential Oil: Chemical Constituents and Antitumor Activity in MDA-MB-231 Cells through PI3K/Akt/mTOR Signaling Pathway

Chamomile essential oil (CEO) is extracted from chamomile and mainly used in aromatherapy. The chemical constituents and its antitumor activity on Triple-negative breast cancer (TNBC) was explored in the present study. Gas chromatography-mass spectrometry (GC/MS) was employed to analyze the chemical constituents of CEO. The cell viability, migration and invasion of TNBC cell MDA-MB-231 were measured using MTT, wound scratch and Transwell assay, respectively. The protein expression of PI3K/Akt/mTOR signaling pathway was determined by Western blot. CEO is rich in terpenoids (63.51 %), among which the identified terpenoids and their derivatives are mainly Caryophyllene (29.57 %), d-Cadinene (12.81 %), Caryophyllene oxide (14.51 %), etc. Three concentration of CEO (1, 1.5, 2 μg/mL) significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells with a dose dependent manner. Moreover, the phosphorylation of PI3K, Akt and mTOR was inhibited by CEO. The results revealed that there was abundant terpenoids in the CEO which account for 63.51 %. CEO significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells, exhibiting antitumor effect on TNBC. The antitumor effect of CEO might attribute to its inhibition on PI3K/Akt/mTOR signaling pathway. However, further study should be conducted in more TNBC cell lines and animal models to provide further evidence for TNBC treatment by CEO.     

IL-7 splicing variant IL-7δ5 induces human breast cancer cell proliferation via activation of PI3K/Akt pathway

Various tumor cells express interleukin 7 (IL-7) and IL-7 variants. IL-7 has been confirmed to stimulate solid tumor cell proliferation. However, the effect of IL-7 variants on tumor cell proliferation remains unclear. In this study, we evaluated the role of IL-7δ5 (an IL-7 variant lacking exon 5) on proliferation and cell cycle progression of human MDA-MB-231 and MCF-7 breast cancer cells. The results showed that IL-7δ5 promoted cell proliferation and cell cycle progression from G1 phase to G2/M phase, associated with upregulation of cyclin D1 expression and the downregulation of p27(kip1) expression. Mechanistically, we found that IL-7δ5 induced the activation of Akt. Inhibition of PI3K/Akt pathway by LY294002 reversed the proliferation and cell cycle progression of MDA-MB-231 and MCF-7 cells induced by IL-7δ5. In conclusion, our findings demonstrate that IL-7δ5 variant induces human breast cancer cell proliferation and cell cycle progression via activation of PI3K/Akt pathway. Thus, IL-7δ5 may be a potential target for human breast cancer therapeutics intervention.     

紫丁香苷调控PI3K/Akt/mTOR信号通路诱导乳腺癌细胞凋亡的研究

目的 研究紫丁香苷的抗乳腺癌作用及分子机制，为紫丁香苷的临床应用提供理论依据。方法 MTT检测紫丁香苷对乳腺癌细胞增殖的抑制作用；台盼蓝、TUNEL和Annexin V-FITC/PI染色检测细胞的凋亡状况，Western bolt检测Caspase-3的活化情况，判断细胞凋亡是否发生；检测凋亡相关蛋白B淋巴细胞瘤2（Bcl-2）的表达，结合JC-1染色探讨紫丁香苷对线粒体凋亡途径的影响；运用PI3K激动剂Recilisib做对比，qRT-PCR和Western bolt检测紫丁香苷调控PI3K/Akt/mTOR通路诱导癌细胞凋亡的作用。结果 紫丁香苷对乳腺癌细胞的增殖具有时间和剂量依赖的抑制作用，能诱导癌细胞发生凋亡。进一步研究发现，紫丁香苷处理后，细胞内Caspase-3被激活，Bcl-2表达下降，线粒体膜电位明显丧失，PI3K、Akt和mTOR的mRNA与蛋白质水平表达无明显变化，但蛋白质磷酸化水平明显下降；Recilisib处理后部分抵消了紫丁香苷对乳腺癌细胞凋亡的作用。结论 紫丁香苷对乳腺癌细胞MDA-MB-231和MCF-7具有良好的抑制作用，其通过抑制PI3K/Akt/mTOR信号通路的活化来抑制细胞增殖并诱导细胞发生线粒体途径的凋亡。紫丁香苷是具有开发潜力的抗乳腺癌药物。     

Chetomin induces apoptosis in human triple-negative breast cancer cells by promoting calcium overload and mitochondrial dysfunction

Human triple-negative breast cancer (TNBC) is poorly diagnosed and unresponsive to conventional hormone therapy. Chetomin (CHET), a fungal metabolite synthesized by Chaetomium cochliodes, has been reported as a promising anticancer and antiangiogenic agent but the complete molecular mechanism of its anticancer potential remains to be elucidated. In our study, we explored the anti-neoplastic action of CHET on TNBC cells. Cytotoxicity studies were performed in human TNBC cells viz. MDA-MB-231 and MDA-MB-468 cells by Sulforhodamine B assay. It exhibited antiproliferative response and induced apoptosis in both the cell types. Cell cycle analysis revealed that it increases the sub G0/G1 phase cell population. Modulation of mitochondrial membrane potential, activation of caspase 3/7 and a remarkable increase in the expression of cleaved PARP and increased chromatin condensation was observed after CHET treatment in MDA-MB-231 and MDA-MB-468 cells. Additionally, an elevated level of intracellular Ca²⁺ played an important role in CHET mediated cell death response. Calcium overload in mitochondria led to release of cytochrome c which in turn triggered caspase-3 mediated cell death. Inhibition of calcium signalling using BAPTA-AM reduced apoptosis confirming the involvement of calcium signalling in CHET induced cell death. Chetomin also inhibited PI3K/mTOR cell survival pathway in human TNBC cells. The overall findings suggest that Chetomin inhibited the growth of human TNBC cells by caspase-dependent apoptosis and modulation of PI3K/mTOR signalling and could be used as a novel chemotherapeutic agent for the treatment of human TNBC in future.     

Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer

Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.     

Novel 4-aminoquinazoline derivatives induce growth inhibition,cell cycle arrest and apoptosis via PI3Kα inhibition

Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα, β, γ, δ), the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kα has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kα distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kα kinase activity with an IC₅₀ of 13.6?nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kα inhibition.     

Arachidonic acid promotes migration and invasion through a PI3K/Akt-dependent pathway in MDA-MB-231 breast cancer cells

Arachidonic acid (AA) is a common dietary n−6 cis polyunsaturated fatty acid that under physiological conditions is present in an esterified form in cell membrane phospholipids, however it might be present in the extracellular microenvironment. AA and its metabolites mediate FAK activation, adhesion and migration in MDA-MB-231 breast cancer cells. However, it remains to be investigated whether AA promotes invasion and the signal transduction pathways involved in migration and invasion. Here, we demonstrate that AA induces Akt2 activation and invasion in MDA-MB-231 cells. Akt2 activation requires the activity of Src, EGFR, and PIK3, whereas migration and invasion require Akt, PI3K, EGFR and metalloproteinases activity. Moreover, AA also induces NFκB-DNA binding activity through a PI3K and Akt-dependent pathway. Our findings demonstrate, for the first time, that Akt/PI3K and EGFR pathways mediate migration and invasion induced by AA in MDA-MB-231 breast cancer cells.     

Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G₁ phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21^Waf1/Cip1 and p27^Kip1; and knockdown of p27^kip1 with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.     

Up-regulation of PI3K/Akt signaling by 17beta-estradiol through activation of estrogen receptor-alpha, but not estrogen receptor-beta, and stimulates cell growth in breast cancer cells

Estrogen stimulates cell proliferation in breast cancer. The biological effects of estrogen are mediated through two intracellular receptors, estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta). However, the role of ERs in the proliferative action of estrogen is not well established. Recently, it has been known that ER activates phosphatidylinositol-3-OH kinase (PI3K) through binding with the p85 regulatory subunit of PI3K. Therefore, possible mechanisms may include ER-mediated phosphoinositide metabolism with subsequent formation of phosphatidylinositol-3,4,5-trisphosphate (PIP(3)), which is generated from phosphatidylinositol 4,5-bisphosphate via PI3K activation. The present study demonstrates that 17beta-estradiol (E2) up-regulates PI3K in an ERalpha-dependent manner, but not ERbeta, and stimulates cell growth in breast cancer cells. In order to study this phenomenon, we have treated ERalpha-positive MCF-7 cells and ERalpha-negative MDA-MB-231 cells with 10nM E2. Treatment of MCF-7 cells with E2 resulted in a marked increase in PI3K (p85) expression, which paralleled an increase in phospho-Akt (Ser-473) and PIP(3) level. These observations also correlated with an increased activity to E2-induced cell proliferation. However, these effects of E2 on breast cancer cells were not observed in the MDA-MB-231 cell line, indicating that the E2-mediated up-regulation of PI3K/Akt pathway is ERalpha-dependent. These results suggest that estrogen activates PI3K/Akt signaling through ERalpha-dependent mechanism in MCF-7 cells.     

Benzo[b]furan derivatives induces apoptosis by targeting the PI3K/Akt/mTOR signaling pathway in human breast cancer cells

The PI3K/Akt/mTOR signaling pathway plays a key regulatory function in cell survival, proliferation, migration, metabolism and apoptosis. Aberrant activation of the PI3K/Akt/mTOR pathway is found in many types of cancer and thus plays a major role in breast cancer cell proliferation. In our previous studies, benzo[b]furan derivatives were evaluated for their anticancer activity and the lead compounds identified were 26 and 36. These observations prompted us to investigate the molecular mechanism and apoptotic pathway of these lead molecules against breast cancer cells. Benzo[b]furan derivatives (26 and 36) were evaluated for their antiproliferative activity against human breast cancer cell lines MCF-7 and MDA MB-231. These compounds (26 and 36) have shown potent efficiency against breast cancer cells (MCF-7) with IC₅₀ values 0.057 and 0.051 μM respectively. Cell cycle analysis revealed that these compounds induced cell cycle arrest at G2/M phase in MCF-7 cells. Western blot analysis revealed that these compounds inhibit the PI3K/Akt/mTOR signaling pathway and induced mitochondrial mediated apoptosis in human breast cancer cells (MCF-7).     

Nimbolide inhibits IGF‐I‐mediated PI3K/Akt and MAPK signalling in human breast cancer cell lines (MCF‐7 and MDA‐MB‐231)

The insulin‐like growth factor I (IGF‐I) signalling pathway contributes a major role on various cancer cell proliferation, survival and cell cycle. The present study was aimed to investigate the effect of nimbolide on IGF signalling and cell cycle arrest in MCF‐7 and MDA‐MB‐231 breast cancer cell lines. The protein expression of IGF signalling molecules and cell cycle protein levels was assessed by western blot analysis. In order to study the interaction of nimbolide on IGF‐1 signalling pathway, IGF‐I and phosphoinositide 3‐kinase (PI3K) inhibitor (LY294002) were used to treat MCF‐7 and MDA‐MB‐231 cells. Further, the cell cycle arrest was analysed by flow cytometry. The protein expression of IGF signalling molecules was significantly decreased in nimbolide‐treated breast cancer cells. PI3K inhibitor and IGF‐I with nimbolide treatment notably inhibited phosphorylated Akt. The cell cycle arrest was observed at the G0/G1 phase, and accumulation of apoptotic cells was observed in nimbolide‐treated breast cancer cell lines. Nimbolide also increased the protein expression of p21 and decreased the cyclins in both the cell lines. Nimbolide decreases the proliferation of breast cancer cells by modulating the IGF signalling molecules, which could be very useful for the breast cancer treatment. Copyright © 2014 John Wiley & Sons, Ltd.     

Platycodin D inhibits migration,invasion, and growth of MDA-MB-231 human breast cancer cells via suppression of EGFR-mediated Akt and MAPK pathways

Platycodin D (PD), an active triterpenoid saponin from Platycodon grandiflorum, has been known to inhibit the proliferation of a variety of cancer cells, but the effect of PD on the invasiveness of cancer cells is largely unknown. In this study, we first determined the molecular mechanism by which PD inhibits the migratory and invasive abilities of the highly metastatic MDA-MB-231 breast cancer cell line. We demonstrated that a non-cytotoxic concentration of PD markedly suppressed wound healing migration, invasion through the matrigel, and adhesion to an ECM-coated substrate in a dose-dependent manner. Moreover, PD inhibited cell invasion by reducing matrix metalloproteinase (MMP)-9 enzyme activity and mRNA expression. Western blot analysis indicated that PD potently suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) as well as blocked the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway. Furthermore, PD treatment inhibited the DNA binding activity of NF-κB, which is known to mediate the expression of epidermal growth factor receptor (EGFR), as observed by electrophoretic mobility shift assay. Specific mechanisms of action exerted by PD involved the downregulation of EGFR and the inhibition of EGF-induced activation of the EGFR, MAPK, and PI3K/Akt pathways. The in vivo studies showed that PD significantly inhibited the growth of MDA-MB-231 xenograft tumors in BALB/c nude mice. These results suggest that PD might be a potential therapeutic candidate for the treatment of breast cancer metastasis.     

All-trans-retinoid acid induces the differentiation of P19 cells into neurons involved in the PI3K/Akt/GSK3β signaling pathway

The pluripotent mouse embryonal carcinoma cell line P19 is widely used as a model for research on all-trans-retinoid acid (RA)-induced neuronal differentiation; however, the signaling pathways involved in this process remain unclear. This study aimed to reveal the molecular mechanism underlying the RA-induced neuronal differentiation of P19 cells. Real-time quantitative polymerase chain reaction and Western blot analysis were used to determine the expression of neuronal-specific markers, whereas flow cytometry was used to analyze cell cycle and cell apoptosis. The expression profiles of messenger RNAs (mRNAs) in RA-induced neuronal differentiation of P19 cells were analyzed using high-throughput sequencing, and the functions of differentially expressed mRNAs (DEMs) were determined by bioinformatics analysis. RA induced an increase in both class III β-tubulin (TUBB3) and neurofilament medium (NEFM) mRNA expression, indicating that RA successfully induces neuronal differentiation of P19 cells. Cell apoptosis was not affected; however, cell proliferation decreased. We found 4117 DEMs, which were enriched in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, Wnt signaling pathway, and cell cycle. Particularly, a few DEMs could be identified in the PI3K/Akt signaling pathway networks, such as PI3K, Akt, glycogen synthase kinase-3β (GSK3β), cyclin-dependent kinase 4 (CDK4), P21, and Bax. RA significantly increased the protein expression of PI3K, Akt, phosphorylated Akt, GSK3β, phosphorylated GSK3β, CDK4, and P21, but it reduced Bax protein expression. The Akt inhibitor affected the increase of TUBB3 and NEFM mRNA expression in RA-induced P19 cells. The molecular mechanism underlying the RA-induced neuronal differentiation of P19 cells is potentially involved in the PI3K/Akt/GSK3β signaling pathway. The decreased cell proliferation ability of neuronally differentiated P19 cells could be associated with the expression of cell cycle proteins.     

Crystal structure of bacterial cell-surface alginate-binding protein with an M75 peptidase motif

Receptor activator of NF-κB (RANK) and RANK ligand (RANKL) are known to play an important role in the development and progression of breast cancer. However, the mechanisms by which stimuli regulate the expression of RANK and RANKL in breast cancer cells are largely unknown. In this study, we show that hypoxia, a common feature of malignant tumors, can enhance the expression of RANK and RANKL mRNA and protein in MDA-MB-231 and MCF-7 breast cancer cells. In addition, we found that hypoxia induced hypoxia-inducible factor-1 alpha (HIF-1α) and phosphorylation of Akt, resulting in upregulation of RANK and RANKL expression; HIF-1α-targeted siRNA and PI3K-Akt inhibitor abrogated this upregulation in MDA-MB-231 cells. Furthermore, we also observed that hypoxia accelerated RANKL-mediated cell migration, which was inhibited following HIF-1α knockdown and PI3K-Akt inhibition. Thus, we provide evidence that hypoxia upregulates RANK and RANKL expression and increases RANKL-induced cell migration via the PI3K/Akt-HIF-1α pathway.     

Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor

The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (−)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with K_i values of 380 and 320 nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG.     

Prosaposin对细胞增殖和凋亡的调控及其分子机制

为研究鞘脂激活蛋白原(Prosaposin)对细胞增殖、细胞凋亡的调控及其可能的分子机制, 以pcDNA3.1 in NIH3T3阴性对照细胞株和过表达prosaposin的Psap-Myc in NIH3T3细胞株为模型, 噻唑蓝(MTT)比色法检测prosaposin对细胞增殖的影响; Annexin V联合碘化丙啶(Propidium iodide, PI)法检测血清饥饿状态下prosaposin对细胞凋亡的影响; Western blotting检测PI3K/Akt信号通路中蛋白磷酸化水平的变化; Real-time PCR检测PI3K/Akt信号通路下游靶分子表达水平的改变。结果表明prosaposin可活化PI3K/Akt信号通路, 提高Akt^Ser473的磷酸化水平, 抑制细胞周期抑制基因P27^KIP1的表达, 上调细胞周期蛋白Cyclin D1的表达, 促进细胞周期从G1→S期进展; 诱导survival基因cIAP1、cIAP2的表达, 促进细胞存活。这些结果提示, prosaposin对细胞增殖和凋亡的调控可能是通过PI3K/Akt信号通路及其下游靶分子进行的。     

Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy

A novel guaiane sesquiterpene derivative, guai-2-en-10α-ol, from Ulva fasciata Delile exhibits antimicrobial property. U. fasciata extract was reported to exhibit cytotoxicity against cancer. In the present study, we have studied the anticancer potential of the compound, guai-2-en-10α-ol, from U. fasciata. The compound showed selective cytotoxicity toward triple-negative breast cancer (TNBC) cell line (MDA MB-231) in a dose-dependent manner. In treated cells, the apoptotic hallmarks such as formation of apoptotic bodies, cell shrinkage, and nuclear condensation were observed. Many small molecules affect the function of cellular signaling pathways. As EGFR/PI3K/Akt pathway proteins are frequently altered in TNBC, we have studied the gene expression of key proteins of this pathway. The semiquantitative PCR results demonstrated the down-regulated expression of PDPK1 (positive regulator) and Akt (key activator) as well as up-regulated expression of PTEN (negative regulator), which suggested the interaction of guai-2-en-10α-ol with upstream protein. Further investigation showed the down-regulation of both PI3K and EGFR. As EGFR is the most upstream protein of the pathway, its protein level expression was investigated. Western blotting analysis confirmed the down-regulation of p-EGFR expression and activation of apoptosis upon compound treatment. Cell cycle analysis also evidenced the G1 phase arrest, which can be due to the inhibition of cell survival pathway. Computational studies showed the interaction of guai-2-en-10α-ol with Asp855 residue of EGFR kinase domain in active conformation. All these results demonstrate the anticancer potential of guai-2-en-10α-ol through EGFR/PI3K/Akt pathway.     

Curcumin Suppresses Proliferation and Migration of MDA-MB-231 Breast Cancer Cells through Autophagy-Dependent Akt Degradation

Previous studies have evidenced that the anticancer potential of curcumin (diferuloylmethane), a main yellow bioactive compound from plant turmeric was mediated by interfering with PI3K/Akt signaling. However, the underlying molecular mechanism is still poorly understood. This study experimentally revealed that curcumin treatment reduced Akt protein expression in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells, along with an activation of autophagy and suppression of ubiquitin-proteasome system (UPS) function. The curcumin-reduced Akt expression, cell proliferation, and migration were prevented by genetic and pharmacological inhibition of autophagy but not by UPS inhibition. Additionally, inactivation of AMPK by its specific inhibitor compound C or by target shRNA-mediated silencing attenuated curcumin-activated autophagy. Thus, these results indicate that curcumin-stimulated AMPK activity induces activation of the autophagy-lysosomal protein degradation pathway leading to Akt degradation and the subsequent suppression of proliferation and migration in breast cancer cell.