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  • Many studies support that Gli transcription factors

    2022-08-05

    Many studies support that Gli transcription factors are not solely regulated by Hh/smo signaling but are also influenced by crosstalk with other pathways, such as RAS, PI3K/AKT, transforming growth factor-b/SMAD, PKC, or extracellular signal-regulated kinase pathways which are downstream and independent of smo [34], [35], [36], [37], [38]. Based on the assumption that Gli activation independent of smo in AML GKT137831 was responsible for the unresponse to cyclopamine, we found that there was no smo protein expression and Gli expression cannot be regulated by cyclopamine or rSHH in HL-60 cells. Previous studies have shown that smo mRNA is also absent in HL-60 cells. Meanwhile smo is present in K562 cells and K562 cells are sensitive to cyclopamine or rSHH. Our study support Gli and smo are not totally conservative in AML. In fact, previous data suggest that even in normal hematopoiesis, Gli1 and smo may not be functionally redundant. One explanation is that the expression of Gli or smo dependent on the differentiation extent of AML cells. Most CD34+ AML cells express smo and CD34− cells do not. Further studies will be necessary to clarify this hypothesis. The cross-talk between the Hh pathway and other cancer relevant pathways has been extensively studied. PI3K and AKT activities are essential for ligand dependent Shh signaling in the specification of neuronal fates in chicken neural explants and chondrogenic differentiation of 10T1/2 cells, and that upregulation of the Gli reporter gene by PI3K/AKT activation is mediated by controlling PKA activity via GSK3β but not mTOR [39]. There also is a report that PI3K/AKT contributes to activation of the HH/GLI1 signaling pathway in ALK-positive anaplastic large cell lymphoma (ALCL), but not in ALK-negative ALCL. And the regulation also has been proved is via GSK3β [16]. Recently, inhibition of mTOR or p70S6K2 has been reported, which can down-regulate Hh/Gli pathway in non-small cell lung cancer cells. Our study provides evidence that the mTOR pathway contributes to the activation of the Hh/Gli cascade in AML cells. Though the mechanism relating to the regulation observed in this study is not yet clear, rapamycin may directly regulate Gli protein stabilization. The combined use of inhibitors of hedgehog signaling and other signaling pathways has been considered as a promising strategy for cancer treatment, including ErbB, Notch, epidermal growth factor receptor, hepatocyte growth factor and ERK1/2 [40], [41], [42], [43], [44]. Recently, it is reported that the combined blockade of hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic cancer stem cells, but neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the cancer cells and the molecular mechanism is still unknown [45]. Another previous study reported that rapamycin can inhibit growth of cells line with Gli expression, the mechanism is also unknown [46]. Moreover inhibition of PI3K pathway interferes with resistance to smoothened antagonists in medulloblastoma, it is unknown if this regulation is via mTOR [47]. One regulation mechanism has been reported is that rapamycin regulates the nuclear localization and activity of the transcription factor Gli3 [48]. And the regulation of rapamycin to Gli1 or Gli2 expressions reported here provides another regulation mechanism. Meanwhile, our study found that combination of GANT61 and rapamycin can markedly diminish AML cells. Previous data support that rapamycin alone has only a modest effect on AML cell survival in liquid culture, and it markedly down-regulated AML blast clonogenicity while sparing or restoring normal hematopoietic precursors [49], [50]. Considering the latent toxicity of GANT61 to normal hematopoietic stem cell, combination of GANT61 and rapamycin may decrease toxic effect of GANT61 on normal hematopoiesis. Rapamycin and GANT61 both influence cell cycle suggesting that rapamycin might show its effect in part via the down regulation of Gli, which should be further examined [51]. Taken together, the combined GANT61 and rapamycin may increase cytotoxic effect on AML cells and decreases toxic effect on normal hemapoietic stem cell, and provide an alternative choice for treatment of AML or even other cancers in the future.