Blockade of sonic hedgehog signaling decreases viability and induces apoptosis in retinoblastoma cells: The key role of the PI3K/Akt pathway

Abstract

Retinoblastoma (RB) is the most common type of malignant intraocular cancer in teenagers. One of the proteins abnormally expressed during oncogenesis of RB is sonic hedgehog (SHH), which possesses the capability to selectively activate transcription factors of different genes. However, the detailed function of SHH in RB remains unknown. Thus, the present study sought to investigate the role of SHH in the development of RB. The human RB WERI-Rb-1 cell line was used as an in vitro model for the knockdown of SHH by a specific short hairpin RNA (shRNA). To assess the effect of SHH inhibition on cell growth and apoptosis, cell viability, colony formation and flow cytometry assays were conducted. WERI-Rb-1 cells transfected with an shRNA targeting SHH were treated with the phosphoinositide-3 kinase (PI3K)/Akt agonist insulin-like growth factor 1 (IGF-1) to investigate the possible mechanism by which SHH promotes RB. The present results revealed that the silencing of SHH induced G1 cell-cycle arrest and apoptosis in WERI-Rb-1 cells and led to a decrease in cell viability, indicating that SHH has a critical role in the determination of RB cell survival. Moreover, according to the results of the IGF-1 assays, suppression of PI3K/Akt was a prerequisite for SHH inhibition, illuminating its potential role in the treatment of RB. The findings outlined in the present study elucidate a clear link between SHH and the PI3K/Akt pathway in RB cell survival, which could provide valuable inspiration for the advancement of therapies against RB.

Combined inhibition of sonic Hedgehog signaling and histone deacetylase is an effective treatment for liver cancer

“…The PI3K/mTOR signaling pathway is closely related to SHH (31). Studies have indicated that the PI3K/mTOR signaling has a synergistic effect on SHH signaling in embryonic development and cancer (21,31). To further investigate the relationship between the PI3K/mTOR and SHH pathways in liver cancer, the results in the present study clearly revealed that combined use of SHH and HDAC inhibitors blocked the activation of the PI3K/mTOR pathway and played an antitumor role.…”

“…It has been reported that inhibition of SHH signaling regulated pancreatic tumorigenesis via inhibition of the PI3K/AKT signaling pathway (21). Thus, it was investigated whether the dual inhibition of the SHH pathway and HDAC inhibited the growth of liver cancer cells via inhibition of the PI3K/AKT signaling pathway.…”

MicroRNA‑361‑3p regulates retinoblastoma cell proliferation and stemness by targeting hedgehog signaling

“…In the current study, Y79 and Weri-Rb-1 cells were utilized. However, these cell lines are in suspension and are thus difficult to use for the assessment of cell migration and invasion (6,28). For this reason, the current study only assessed cell proliferation and stemness, which serves as a limitation.…”

“…Furthermore, Bai et al (11) revealed that miR-125b promotes tumor growth and suppresses apoptosis by targeting DNA Damage Regulated Autophagy Modulator 2 in RB. SHH signaling is another major pathway that is dysregulated in RB (6,25). SHH, a vertebrate homologue of the Drosophila segment polarity gene product, hedgehog, is associated with retina cell proliferation and differentiation during the process of embryonic development (37,38).…”

“…However, the most common treatment protocol includes chemotherapy combined with immunotherapy, which is cytotoxic to RB cells (5). However, this treatment produces various adverse effects, including the acceleration of RB progression, meaning that the development of other therapeutic methods, particularly those that target specific signaling pathways, is required (4,6).…”