Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial–mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

KCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel family, is commonly expressed in a wide range of tissues and cell types. Previous studies indicated that Kir2.1 may be associated with SCLC multidrug resistance (MDR). However, whether Kir2.1 can regulate MDR and its underlying mechanisms remain poorly understood in SCLC. KCNJ2/Kir2.1 expression was examined in tissues from fifty-two SCLC cases by immunohistochemistry. Overexpression or knockdown of KCNJ2/Kir21 was performed in multidrug-resistant SCLC cell lines (H69AR and H446AR) and their parental cell lines (H69 and H446) to assess its influence on cell growth, apoptosis, the cell cycle and chemoresistance. KCNJ2/Kir2.1 was expressed in 44.23% (23/52) of SCLC tissues. Overexpression of KCNJ2/Kir2.1 was correlated with the clinical stage and chemotherapy response in SCLC patients. Knockdown of KCNJ2/Kir2.1 expression using KCNJ2/Kir2.1 shRNA in H69AR and H446AR cells inhibited cell growth and sensitized the cancer cells to chemotherapeutic drugs by increasing cell apoptosis and cell cycle arrest. Forced KCNJ2/Kir2.1 expression in H69 and H446 cells promoted cell growth and enhanced multidrug resistance via reduced drug-induced apoptosis accompanied by cell cycle arrest. KCNJ2/Kir2.1 expression was also influenced by PKC and MEK inhibitors. In addition, multidrug resistance protein 1 (MRP1/ABCC1) was confirmed to interact with KCNJ2/Kir2.1 by Co-IP assays. KCNJ2/Kir2.1 modulates cell growth and drug resistance by regulating MRP1/ABCC1 expression and is simultaneously regulated by the Ras/MAPK pathway and miR-7. KCNJ2/Kir2.1 may be a prognostic predictor and a potentially novel target for interfering with chemoresistance in SCLC.

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. It is well-known that estrogen plays an important role in the pathogenesis of endometrioid endometrial carcinoma (EEC), and induces the cancer suppressor gene PTEN deletion. However, how estrogen affects PTEN expression remains unknown. In the present study, we found in 40 EEC specimens, miR-200c level was higher in most cancer areas than that in the adjacent normal endometrium, while PTEN and PTENP1 were lower. Moreover, the expression of PTEN/PTENP1 and miR-200c also showed a converse relationship in EEC cell lines. In addition, we demonstrated that miR-200c bound directly to PTEN and PTENP1, and PTENP1 could reverse miR-200c inhibition function to PTEN using a dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays. Next, 17β-estradiol (E2) treatment could improve miR-200c and drop the PTEN level, which caused a consequential increase of the phospho-PI3K-AKT pathway genes. When we stably knocked down estrogen receptor α (ERα) expression in the EEC cell line, the effects of E2 on miR-200c and PTEN declined. In addition, it was demonstrated that E2 might modulate cell proliferation, migration and invasion relying on the expression of miR-200c. Taken together, it can be concluded that estrogen improves the miR-200c level by combining with ER, PTENP1 and PTEN could be inhibited by miR-200c, and then activate the PI3K-AKT pathway. This work provided a new mechanism of EEC development and a new potential therapeutic target.

Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung cancer with abnormal expression. Growing evidence indicates that the signaling proteins of EPHA3 downstream, including PI3K, BMX and STAT3, play crucial roles in tumorigenesis and cancer progression. To explore the possible role of EPHA3 in MDR, we assessed the influence of EPHA3 on chemoresistance, cell cycle, apoptosis, and tumor growth, as well as the relationship between EPHA3 and the expression of PI3K, BMX, and STAT3 in SCLC. We observed that overexpression of EPHA3 in SCLC cells decreased chemoresistance by increasing apoptosis and inducing G0/G1 arrest, accompanied by reduced phosphorylation of PI3K/BMX/STAT3 signaling pathway. Knockdown of EPHA3 expression generated a resistant phenotype of SCLC, as a result of decreased apoptosis and induced G2/M phase arrest. And re-expression of EPHA3 in these cells reversed the resistant phenotype. Meanwhile, increased phosphorylation of PI3K/BMX/STAT3 signaling pathway was observed in these cells with EPHA3 deficiency. Notably, both PI3K inhibitor (LY294002) and BMX inhibitor (LFM-A13) impaired the chemoresistance enhanced by EPHA3 deficiency in SCLC cell lines. Furthermore, EPHA3 inhibited growth of SCLC cells in vivo and was correlated with longer overall survival of SCLC patients. Thus, we first provide the evidences that EPHA3 is involved in regulating the MDR of SCLC via PI3K/BMX/STAT3 signaling and may be a new therapeutic target in SCLC.