Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells

ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME2) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME2 on the hepatic lipid content and ABCA1 expression. We found that 2-ME2 dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME2 enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME2 on ABCA1 promoter activity. Further, 2-ME2 stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME2, which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME2 on ABCA1 expression. All of our results demonstrated that 2-ME2 might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.

Glycosidic flavonoids and their potential applications in cancer research: a review

Purpose of review Every year, the cancer patient registry increases, and the leading cause of death in a global context. Plant-based molecules are gaining attention in cancer research due to the side effects of chemotherapy. A glycosidic derivative of flavonoid (GDF) plays a significant role in cancer proliferation mechanisms. GDF inhibits cell proliferation by elevating the expression of apoptotic proteins, altering the expression of nuclear factor-kappa B (NF- κB), and decreasing mitochondrial membrane potential (Δψm) in cancer cells. Recent findings Reported studies on the flavonoids orientin, vitexin, prunetionoside, chrysin, and scutellarein increased attention and are being widely investigated for their potential role in different parts of cancer research. Prunetionoside is a flavonoid with high cytotoxic potential and capable of inducing necroptosis in AGS gastric cancer cells. Similarly, scutellarein is a flavonol, induces an extrinsic apoptotic pathway and downregulates the expression level of cyclin proteins in HepG2 liver cancer cells. Vitexin is reported to be capable of deregulating the expression levels of p-Akt, p-mTOR, and p-PI3K in A549 lung cancer cells. Orientin inhibits IL-8 expression and invasion in MCF-7 breast cancer cells by suppressing MMP-9 in the presence of TPA via STAT3/AP-1/ERK/PKCα-mediated signaling pathways. It also induces mitochondria-mediated intrinsic apoptosis and G0/G1 cell cycle arrest in HT29 colon cancer cells. Chrysin is a flavonoid present in honey that has been shown to play an important role in cervical and colon cancer by suppressing the AKT/mTOR/PI3K pathway and increasing ROS accumulation, LDH leakage, respectively.

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.

Co-delivery of the autophagy inhibitor si-Beclin1 and the doxorubicin nano-delivery system for advanced prostate cancer treatment

Resistance to apoptosis is a key mechanism underlying how cancer cells evade tumor therapy. Autophagy can prevent anticancer drug-induced apoptosis and promote tumor resistance. The purpose of this study was to improve the sensitivity and efficacy of chemotherapeutic drugs through the inhibition of autophagy. Hydrophobic doxorubicin–hydrazone–caproyl–maleimide (DOX-EMCH) and autophagy-inhibiting si-Beclin1 were simultaneously delivered via the amphiphilic peptide micelle system (Co-PMs) using poly(L-arginine)–poly(L-histidine)–DOX-EMCH as the copolymer building unit. The constructed micelle system promoted the escape of si-Beclin1 from endosomes and the release of DOX into the nucleus. The Co-PMs exhibited 2.7-fold higher cytotoxicity and proapoptotic ability in PC3 cells than DOX treatment alone, demonstrating that si-Beclin1 could inhibit the autophagic activity of prostate cancer (PCa) cells by targeting the type III PI3K pathway and enhance the sensitivity of the cells to the chemotherapeutic drug DOX. In addition, the peptide micelles successfully passively targeted DOX and si-Beclin1 to the tumor tissue. Compared with DOX or si-Beclin1 treatment alone, the Co-PMs showed a 3.4-fold greater tumor inhibitory potential in vivo, indicative of a significant antiproliferative effect. Our results suggested that the Co-PMs developed in this study have the potential to combine autophagy inhibition and chemotherapy in cancer treatment, especially for PCa.

Circadian Gene cry Controls Glioblastoma Tumorigenesis through Modulation of myc Expression

Glioblastoma (GB) is the most frequent malignant brain tumor among adults and currently there is no effective treatment. It is a very aggressive tumor that grows fast and spreads through the brain causing the death of patients in 15 months. GB cells mutate frequently and generate a heterogeneous population of tumoral cells genetically distinct. Thus, the contribution of genes and signaling pathways relevant for GB progression is of great relevance. We use a Drosophila model of GB that reproduces the features of human GB, and describe the upregulation of the circadian gene cry in GB patients and in a Drosophila GB model. We study the contribution of cry to the expansion of GB cells, to the neurodegeneration caused by GB, and to premature death and determine that cry is required for GB progression. Moreover, we analyze the mechanisms that regulate cry expression by the PI3K pathway. Finally, we conclude that cry is necessary and sufficient to regulate myc expression in GB. These results contribute to the understanding of the signals that impulse GB malignancy and lethality and open novel opportunities for the treatment of GB patients.

Targeting PI3K/Akt signal transduction for cancer therapy

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.