Abstract
By using human melanoma and glioblastoma cell lines and their derivative BCL-XL overexpressing clones, we investigated the role of BCL-XL in aggressive features of these two tumor histotypes. We found that in both models, BCL-XL overexpression increased in vitro cell migration and invasion and facilitated tumor cells to form de novo vasculogenic structures. Furthermore, BCL-XL overexpressing cells exhibited higher tumors sphere formation capacity and expressed higher levels of some stem cell markers, supporting the concept that BCL-XL plays essential roles in the maintenance of cancer stem cell phenotype. BCL-XL expression reduction by siRNA, the exposure to a BCL-XL-specific inhibitor and the use of a panel of human melanoma cell lines corroborated the evidence that BCL-XL regulates tumor progression-associated properties. Finally, the vascular markers and the vasculogenic mimicry were up-regulated in the BCL-XL overexpressing xenografts derived from both tumor histotypes. In conclusion, our work brings further support to the understanding of the malignant actions of BCL-XL and, in particular, to the concept that BCL-XL promotes stemness and contributes to the aggressiveness of both melanoma and glioblastoma.
Highlights
A growing body of results supports the evidence thatBCL-XL, and more in general BCL-2 family members, are key regulators of apoptosis, and actively participate in the regulation of other vital cellular functions
We previously identified a novel function of BCL-XL in promoting tumor angiogenesis through the nuclear factor kappa B (NF-kB)/interleukin 8 (CXCL8) axis in tumor cell lines with a different origin, including glioblastoma and melanoma[12,13,14]
To further explore the molecular pathway involved in BCL-XL-mediated tumor aggressiveness, we focused our attention on HIF-1/VEGF axis, a key pathway involved in melanoma and glioblastoma vascularization and aggressiveness[31,36,37,38,39,40]
Summary
A growing body of results supports the evidence that. BCL-XL, and more in general BCL-2 family members, are key regulators of apoptosis, and actively participate in the regulation of other vital cellular functions. As a consequence, limiting the oncogenic properties of the anti-apoptotic proteins of this family to their ability to oppose apoptosis is an old concept. Several pieces of evidence indicate that BCL-XL elicits new functions, which are genetically distinct from its effect on apoptosis[1,2,3]. A pivotal role for BCL-XL in vitro and in vivo invasion of malignant glioma[2], colorectal carcinoma[4], and breast carcinoma[1, 5] has been described. The ability of BCL-XL protein to Official journal of the Cell Death Differentiation Association
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