Abstract
Emerging evidence supporting the activation of the Akt-mammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment. Indeed, rapamycin, a clinically relevant mTOR inhibitor, promotes the rapid regression of HNSCC-tumor xenografts in mice. However, rapamycin does not affect the growth of HNSCC cells in vitro, thus raising the possibility that, as for other cancer types, rapamycin may not target cancer cells directly but may instead act on a component of the tumor microenvironment, such as tumor-associated vasculature. Here, we used a retroinhibition approach to assess the contribution of cancer cell-autonomous actions of rapamycin to its antitumor activity in HNSCC. A rapamycin-resistant form of mTOR (mTOR-RR) was expressed in HNSCC cells while retaining the wild-type (rapamycin-sensitive) mTOR (mTOR-WT) alleles in host-derived endothelial and stromal cells. Expression of mTOR-RR prevented the decrease in phospho-S6 levels caused by rapamycin through mTOR in HNSCC cells but not in stromal cells, and rendered HNSCC xenografts completely resistant to the antitumoral activity of rapamycin. This reverse pharmacology strategy also enabled monitoring the direct consequences of inhibiting mTOR in cancer cells within the complex tumor microenvironment, which revealed that mTOR controls the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the consequent expression of vascular endothelial growth factor and a glucose transporter, Glut-1, in HNSCC cells. These findings indicate that HNSCC cells are the primary target of rapamycin in vivo, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells.
Highlights
A better understanding of the molecular basis of cancer has provided the rationale for the development of novel therapeutic strategies to prevent and treat human malignancies
We provide evidence that the blockade of mTOR in head and neck squamous cell carcinoma (HNSCC) cells prevents the accumulation of the transcription factor hypoxia-inducible factor-1α (HIF-1α), thereby reducing the expression of key molecules involved in cellular glucose metabolism, such as the cell surface expression of glucose transporter, Glut-1 and the maintenance of the tumor vascularity, the latter by decreasing the expression of proangiogenic mediators such as VEGF
Rapamycin is a selective inhibitor of the mTOR pathway that has been approved by the Food and Drug Administration for nearly 10 years based on its immunosuppressive and antirestenosis properties [23]
Summary
A better understanding of the molecular basis of cancer has provided the rationale for the development of novel therapeutic strategies to prevent and treat human malignancies. In this regard, emerging evidence suggests that the aberrant activity of the Akt-mTOR signaling pathway is a frequent event in some of the most prevalent human cancers [1, 2]. While hereditary mutations in genes leading to overactivity of Akt-mTOR increase cancer susceptibility, the acquisition of sporadic mutations or altered expression and activity of molecules regulating the Akt-mTOR pathway are frequent events in human malignancies, underscoring the importance of this signaling route in cancer development
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