Abstract
The clinical benefits of a Hedgehog (Hh) inhibitor, LDE225 (NPV-LDE-225, Erismodegib), have been unclear in hematological cancers. Here, we report that LDE225 selectively inhibited migration and adhesion of mantle cell lymphoma (MCL) to bone marrows via very late antigen-4 (VLA-4) mediated inactivation of focal adhesion kinase (FAK) signaling. LDE225 treatment not only affected MCL cells, but also modulated stromal cells within the bone marrow microenvironment by decreasing their production of SDF-1, IL-6 and VCAM-1, the ligand for VLA-4. Surprisingly, LDE225 treatment alone did not suppress cell proliferation due to increased CXCR4 expression mediated by reactive oxygen species (ROS). The increased ROS/CXCR4 further stimulated autophagy formation. The combination of LDE225 with the autophagy inhibitors further enhanced MCL cell death. Our data, for the first time, revealed LDE225 selectively targets MCL cells migration and adhesion to bone marrows. The ineffectiveness of LDE225 in MCL is due to autophagy formation, which in turn increases cell viability. Inhibiting autophagy will be an effective adjuvant therapy for LDE225 in MCL, especially for advanced MCL patients with bone marrow involvement.
Highlights
Despite several new pharmacological compounds were approved for mantle cell lymphoma (MCL) in the past decade, significant numbers of the patients are still relapsing after treatment
We discovered that LDE225 targeted cell migration and adhesion of MCL cells to bone marrow stromal cells (BMSCs) without affecting cell viability
Given that advanced MCL cells are dispersed to bone marrows, our results suggest LDE225 could be used to selectively inhibit MCL dispersal
Summary
Despite several new pharmacological compounds were approved for MCL in the past decade, significant numbers of the patients are still relapsing after treatment. Hedgehog-mediated signaling has been shown to promote growth and dissemination of several human solid cancers [2,3,4,5,6,7,8,9,10,11,12,13] as well as tumor growth in hematological malignancies [2,3,4]. These observations indicate that aberrant activation of the Hh signaling pathway leads to an increase in cell survival and contributes to the maintenance of metastatic behavior. The most clinically advanced Smo targeting agent is cyclopamine [2, 9,10,11], and GDC-0449 [7, 9, 12], IPI-926 [13, 14] or GANT61 [9, 15] has been used to block Hh signaling
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