The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines

Abstract

ObjectivesTo explore the genetic and molecular events that control subclones exhibiting distinct invasive/migratory capacities derived from human epithelial ovarian cancer (EOC) cell line A2780 and SKOV3.MethodsSingle-cell subclones were isolated and established that were derived from the SKOV3 and A2780 cell lines through limiting dilution methodology. Transwell insert assays and MTT assays were performed to screen and identify the subclones exhibiting the highest and the lowest invasive/migratory capacities, and the selected subclones were renamed as A-H (A2780 high), A-L (A2780 low), S-H (SKOV3 high), and S-L (SKOV3 low). Their biological characteristics were evaluated. RNA-Seq was conducted on the targeted subclones.ResultsCompared with their corresponding counterparts, A-H/S-H cells exhibited significantly higher invasive/migratory capacities (P < 0.001 and = 0.001, respectively). A-H/S-H cells displayed a clear reduction in doubling time (P = 0.004 and 0.001, respectively), and a significant increase in the percentage of cells in S phase (P = 0.004 and 0.022, respectively). Additionally, the apoptotic rates of A-H/S-H cells were significantly lower than those of A-L/S-L cells (P = 0.002 and 0.026, respectively). At both mRNA and protein levels, caspase-3 and caspase-7 expression were reduced but Bcl-2 expression was increased in A-H/S-H cells. The TrkB (anoikis-related) and Beclin1 (autophagy-related) levels were consistently high and low, respectively, in both A-H/S-H cells. Resistance to chemotherapy in vitro and higher capacities on tumor formation in vivo was presented in both A-H/S-H cells. PI3K/AKT/mTOR pathway components, PIK3CA, PIK3CD, AKT3, ECM1, GPCR, mTOR and PRKCB were increased but that the Nur77 and PTEN were decreased in A-H/S-H cells, identified by RNA-Seq and consistently confirmed by RT-PCR and Western blot analyses.ConclusionsHeterogeneous cell subpopulations exhibiting distinct invasive and migratory capacities co-exist within the SKOV3 and A2780 cell lines. PI3K/AKT/mTOR pathway activation is associated with higher invasive and migratory capacities in subpopulations of human ovarian cancer cell lines. Inhibiting this pathway may be useful for the chemoprevention or treatment of EOC.

Dual inhibition of BDNF/TrkB and autophagy: a promising therapeutic approach for colorectal cancer

“…NTs primarily promote cell survival and differentiation by activating either the PI3K/AKT (phosphatidylinositide 3 kinase/Akt) and/or MAPK (mitogenic activated protein kinase) and/or the PLC‐γ (phospholipase C gamma) pathway . TrkB expression and activation have been described for several types of cancers such as lymphomas, breast, lung cancers as reported by our team and others . For CRC, we previously identified the BDNF/TrkB axis as a prosurvival pathway , as already been reported by Brunetto de Farias et al .…”

Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway

“…Evidence indicates that the PI3K/Akt pathway regulates the epithelial-mesenchymal transition, cell cycle, angiogenesis and apoptosis, and has an important role in tumor progression (26)(27)(28). The PI3K/Akt pathway was reported to be activated in PTC and to be involved in cell proliferation and migration (29).…”

Tanshinone IIA Affects Autophagy and Apoptosis of Glioma Cells by Inhibiting Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway

“…Bai et al [34] suggested that the activation of PI3K/Akt/mTOR signaling pathway was related to stronger migratory and invasive capacities in ovarian carcinoma cells. Deng et al [35] proved that the PI3K/Akt/mTOR signaling pathway could be used as a therapeutic target for women breast carcinoma.…”