GANT61 suppresses cell survival, invasion and epithelial-mesenchymal transition through inactivating AKT/mTOR and JAK/STAT3 pathways in anaplastic thyroid carcinoma

Abstract

Glioma-associated oncogene (Gli) antagonist-61 (GANT61) not only suppresses the malignant behavior of several cancers but also presents synergistic effects with other anticancer agents on suppressing the progression of cancers, while relevant information is rare in anaplastic thyroid carcinoma (ATC). This study aimed to explore the therapeutic effect of GANT61 in ATC and its molecular mechanism. ATC cells (8505C and CAL-62) were treated with GANT61, followed by detection of cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) markers. Subsequently, RNA sequencing was performed to explore the potential downstream pathway. Following that, rescue experiments were conducted by SC79 (AKT activator) or colivelin (STAT3 activator) monotreatment or combined with GANT61 in ATC cells. GANT61 reduced Gli1 expression, suppressed proliferation at several time settings, promoted apoptosis, inhibited invasion and increased E-cadherin while decreased Vimentin and Snail expressions (EMT markers) in ATC cells. The subsequent RNA sequence identified 85 upregulated differentially expressed genes (DEGs) and 71 downregulated DEGs in GANT61-treated ATC cells, which were mainly enriched in PI3K/AKT, JAK/STAT, Hedgehog and mTOR pathways. Next, the inactivation of AKT/mTOR and JAK/STAT3 pathways by GANT61 treatment was verified by western blot. The following rescue experiments showed that SC79 or colivelin treatment promoted the malignant behaviors of ATC cells. More importantly, SC79 or colivelin treatment compensated the effect of GANT61 treatment on cell proliferation at several time settings and apoptosis, invasion, and part of that on EMT in ATC cells. GANT61 suppresses cell survival, invasion and EMT through inactivating AKT/mTOR or JAK/STAT3 pathways in ATC.

Platycodin D sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway

“…In vitro experiments showed that the inhibitory effect of CTX on cancer cell proliferation, migration, and invasion was negatively correlated with p-Akt levels. This implies that some downstream components of Akt that are related to migration and invasion, such as mTOR ( 26 )or Glycogen Synthase Kinase 3β (GSK3β)/Snail ( 27 ), may be inhibited by PD. In addition, CTX itself decreases CRC cell migration and invasion to a certain degree, which may interfere with other downstream pathways of EGF/EGFR ( 28 ).…”

Ouabain Effects on Human Anaplastic Thyroid Carcinoma 8505C Cells

“…In 8505C cells, heat shock protein 90, in combination with histone acetyltransferase inhibitor triptolide, reduced cell viability and increased cell death, possibly through the inactivation of mTOR pathway [ 39 ]. Similarly, the combination of baicalein and docetaxel, and glioma-associated oncogene antagonist 61, also appeared to induce anti-cancer effects in 8505C cells through the suppression of the mTOR pathway [ 40 , 41 ]. Contrastingly, metformin diminished the viability of 8505C and induced a slight increase in apoptosis; however, in this case, total mTOR expression was increased [ 42 ].…”

PIKE-A Modulates Mitochondrial Metabolism through Increasing SDHA Expression Mediated by STAT3/FTO Axis

“…LN229 control and PIKE-A knockdown cells were harvested and suspended in 1 mL of TRIzol (Invitrogen, Carlsbad, CA, USA). Then, dry ice was used to transport to Lc-Bio Technologies Co., Ltd. (Hangzhou, China), as described previously [ 28 ].…”