Arsenic-induced oxidative stress and its reversibility

Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer. A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway. Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-κB, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer. The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer.

/pdf/lncrna-ak023391-promotes-tumorigenesis-and-invasion-of-3lz05vadrm.pdf

LncRNA AK023391 promotes tumorigenesis and invasion of gastric cancer through activation of the PI3K/Akt signaling pathway

Bufalin is the active ingredient of the Chinese medicine Chan Su, and it has been reported that bufalin induces apoptosis in some human leukemia and solid cancer cell lines The exact mechanism of bufalin-induced apoptosis is, however, still not clear In this study, we demonstrated that bufalin inhibited the proliferation of gastric cancer MGC803 cells in a dose-dependent and time-dependent manner At a low concentration (20 nmol/l), bufalin induced M-phase cell cycle arrest, whereas at a high concentration (80 nmol/l) it induced apoptosis in MGC803 cells Bufalin increased the Bax/Bcl-2 ratio and activated caspase-3 during the apoptotic process of MGC803 cells It should be noted that bufalin transiently activated the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and then inhibited it completely, and upregulated the Casitas B-lineage lymphoma (Cbl) family of ubiquitin ligases, upstream modulators of PI3K A combination of bufalin and LY294002, a PI3K-specific inhibitor, enhanced apoptosis, but PD98059, an extracellular-regulated protein kinase-specific inhibitor, had no significant effect on bufalin-induced apoptosis These results suggested that the PI3K/Akt pathway might play a key role in bufalin-induced apoptosis in gastric cancer MGC803 cells

PI3K/Akt is involved in bufalin-induced apoptosis in gastric cancer cells.

Background
β-Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anti-cancer effects against a broad spectrum of tumors. The mechanism by which β-elemene kills cells remains unclear. The aim of the present study is to investigate the anti-tumor effect of β-elemene on human gastric cancer cells and the molecular mechanism involved.

/pdf/b-elemene-induced-autophagy-protects-human-gastric-cancer-3ucy5tlxd9.pdf

β-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis

FTY720 (Fingolimod) is a clinically approved immunomodulating therapy for multiple sclerosis that sequesters T-cells to lymph nodes through functional antagonism of sphingosine-1-phosphate 1 receptor. FTY720 also demonstrates a proven efficacy in multiple in vitro and in vivo cancer models, suggesting a potential therapeutic role in cancer patients. A potential anticancer mechanism of FTY720 is through the inhibition of sphingosine kinase 1, a proto-oncogene with in vitro and clinical cancer association. In addition, FTY720's anticancer properties may be attributable to actions on several other molecular targets. This study focuses on reviewing the emerging evidence regarding the anticancer properties and molecular targets of FTY720. While the clinical transition of FTY720 is currently limited by its immune suppression effects, studies aiming at FTY720 delivery and release together with identifying its key synergetic combinations and relevant patient subsets may lead to its rapid introduction into the clinic.

/pdf/the-emerging-role-of-fty720-fingolimod-in-cancer-treatment-1w0lj2c108.pdf

The emerging role of FTY720 (Fingolimod) in cancer treatment.

Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2009.05.054

Ubiquitin ligase Cbl‐b sensitizes leukemia and gastric cancer cells to anthracyclines by activating the mitochondrial pathway and modulating Akt and ERK survival signals

Up-regulation of the Cbl family of ubiquitin ligases is involved in ATRA and bufalin-induced cell adhesion but not cell differentiation.

The ubiquitin ligase Cbl-b is a negative regulator of the PI3K/Akt pathway, the survival pathway implicated in chemotherapy resistance. However, it remains unclear whether Cbl-b can regulate chemosensitivity through modulating Akt activation. In this study, VP-16-induced RBL-2H3 cells apoptosis was accompanied by the activation of Akt and ERK. The PI3K inhibitor LY294002, not the ERK inhibitor PD98059, enhanced the apoptosis. In addition, down-regulation of Cbl-b was also detected. Over expression of Cbl-b significantly enhanced VP-16-induced cell apoptosis with inhibition of Akt activity, while a dominant negative (DN) RING Finger domain mutation completely abolished this enhancement. On the other hand, ERK activity was enhanced by Cbl-b, and the ERK inhibitor PD98059 reversed Cbl-b-enhanced apoptosis. The consistent results were also showed in the process of Ara-c treatment. These observations indicate that Cbl-b promotes RBL-2H3 apoptosis induced by VP-16 or Ara-c, probably through inhibition of Akt and activation of ERK.

Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation

Multiple myeloma (MM) remains incurable by conventional chemotherapy Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720) Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management

Ying-Chun Li

Papers

Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation.

Ubiquitin ligase Cbl‐b sensitizes leukemia and gastric cancer cells to anthracyclines by activating the mitochondrial pathway and modulating Akt and ERK survival signals

Up-regulation of the Cbl family of ubiquitin ligases is involved in ATRA and bufalin-induced cell adhesion but not cell differentiation.

Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation

The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.