Gli1 inhibition suppressed cell growth and cell cycle progression and induced apoptosis as well as autophagy depending on ERK1/2 activity in human chondrosarcoma cells

Abstract

The transcription factor glioma-associated oncogene 1 (Gli1) has been recognized as a very important nuclear executor at the distal end of the Hedgehog (Hh) signal pathway, which has crucial roles in regulating many developmental processes, such as pattern formation, differentiation, proliferation, and apoptosis. Overexpression of patched 1 protein and Gli1 or constitutively active Indian Hedgehog (IHh)-parathyroid hormone-related protein signal pathway may lead to musculoskeletal tumorigenesis. However, for chondrosarcoma few studies have paid close attention to the IHh-Gli1 signal transduction cascade and more work needs to be carried out to fully elucidate Gli1 protein functions. Here we show that the IHh signal pathway was activated in chondrosarcoma, and knocking down the expression of Gli1 attenuated the disturbed IHh signal pathway, which not only suppressed cell proliferation and promoted G2/M cell cycle arrest but also enhanced cell apoptosis by downregulating Bcl-2 and Bcl-xl expression. Furthermore, Gli1 downregulation, not cyclopamine, induced autophagy by regulating mTOR phosphorylation, and inhibition of autophagy prevented Gli1 small interfering RNA-mediated cell death. We also demonstrated that extracellular signal-regulated kinase 1/2 activity may mediate these antiproliferative events induced by Gli1 inhibition. These results indicate that Gli1 inhibition could ultimately provide a promising new approach for chondrosarcoma treatment.

Arsenic trioxide inhibits growth of human chondrosarcoma cells through G2/M arrest and apoptosis as well as autophagy

“…The cells were treated with ATO with indicated condition including co-treatment with 3MA or CQ. Cell viability was analyzed by MTT assay as described previously [15].…”

“…Apoptotic cells were analyzed with Annexin V/FITC kit (BD Biosciences, San Jose, CA, USA) according to the manufacturer's instructions and analyzed by flow cytometry after compound treatment as described previously [15].…”

“…For chondrosarcoma, our previous study indicated that Hh pathway was disturbed in chondrosarcoma. Silencing Gli1 by small interfering RNA (siRNA) suppressed cell growth and cell cycle progression, induced apoptosis and autophagy in chondrosarcoma cells [15].…”

The cell survival pathways of the primordial RNA-DNA complex remain conserved in the extant genomes and may function as proto-oncogenes

“…As to chondrosarcoma, Gli oncoprotein (glioma-associated oncogene 1) activated in the end phase of the Hh pathway was found to be the major inducer of chondroblast dedifferentiation. Small interfering siRNA abolished Gli mRNA translation into oncoprotein, activated ERK (ex- tracellular signal-regulated kinase), stopped cell cycle progression, reduced Ki-67 expression, and induced either apoptosis or auto phagy of the tumor cells [146]. The investigators induced the transition of autophagy into apoptosis; thus, it is not known if the autophagic cells could have possibly redif ferentiated into mesenchymal stem cells or fi broblasts.…”

Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma

“…76 Silencing Gli1 expression in chondrosarcoma activates apoptosis independent of caspase 3 and induces autophagy via mTOR signaling. 98 WWOXmediated apoptosis in p53-mutated U373MG cells is also through the caspase-3-independent pathway; it is worth evaluating whether WWOX triggers apoptosis through the binding to Gli1 in GBM cells.…”