Cell Death Differ: GLI1 mediates the occurrence and development of chondrosarcoma through mTOR/S6K1 signaling cascade

Chondrosarcoma (CS) is a heterogeneous type of primary cartilage malignant tumor, which is characterized by the accumulation of neoplastic chondrogenic cells.
About 85% of CS cases are primary cases.
At present, surgical resection is still a standard intervention for this malignant tumor.

However, due to the limited effects of chemotherapy and radiotherapy, the prognosis of patients is still challenging.
Therefore, there is an urgent need to identify new therapeutic targets and develop effective combination therapy strategies.

Previous studies have shown that Hedgehog (HH) signals play a vital role in embryonic development and postpartum biological processes.
And the abnormality of this pathway and the overexpression of downstream transcription factor GLI1 are highly correlated with a variety of malignant tumors including CS.
Previous studies have shown that knocking down the expression of GLI1 can inhibit the survival of CS cells.
However, the underlying mechanism that regulates GLI1 expression remains unclear.

Simultaneous inhibition of MVP and GLI1 significantly inhibits the growth of CS

In this study, the researchers confirmed that GLI1 participates in the SMO-independent signaling pathway in CS cells.
Through affinity purification experiments, the researchers identified the MVP protein as the binding protein of GLI1.
MVP can promote the nuclear transport and stability of GLI1 by inhibiting the affinity of GLI1 and SUFU inhibitors, and increase the expression of GLI1 through the mTOR/S6K1 signaling cascade.

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Functional studies have shown that knocking down the expression of MVP can inhibit cell growth and induce apoptosis.
Simultaneous inhibition of MVP and GLI1 will significantly inhibit the growth of CS.
In addition, further studies have shown that MVP, GLI1 and P-p70S6K1 are highly expressed in 71 human CS tissues.

All in all, the results of this study reveal a new regulatory mechanism that affects GLI1 expression independent of the HH signaling pathway, and provides a certain theoretical basis for the combination therapy of advanced CS patients.