RT info:eu-repo/semantics/article
T1 Pam3CSK4, a TLR2 ligand, induces differentiation of  glioblastoma stemcells and confers susceptibility to temozolomide
A1 Megías Vericat, Javier
A1 Martínez, Alba
A1 San-Miguel, Teresa
A1 Gil-Benso, Rosario
A1 Muñoz Hidalgo, Lisandra
A1 Albert-Bellver, David
A1 Carratalá, Amara
A1 Gozalbo, Daniel
A1 López Ginés, Concha
A1 Gil, María Luisa
A1 Cerdá-Nicolás, Miguel J.
K1 Pam3CSK4
K1 Glioblastoma stem cells
K1 Toll-like receptors
K1 TLR2
K1 Stem cell differentiation
AB Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimulation by TLR ligands on promoting GSC differentiation into mature GBM cells. First, our results showed heterogeneous TLR expression by GBM cells from human tumors and, for the first time, by human GSCs defined by their CD133+ and CD44+ phenotypes. Next, the effect of TLR ligands was studied in in vitro cell cultures of neurospheres and CD44+ cells obtained from two GBM cell lines (U-87 and U-118). The expression of GSC markers diminished in the presence of Pam3CSK4 or LPS (TLR2 and TLR4 ligands, respectively), thus indicating TLR-dependent differentiation. Interestingly, simultaneous treatment with Pam3CSK4 plus temozolomide (TMZ), the reference drug in GBM treatment, significantly increased cell death compared to the effect of the ligand alone, which showed no toxicity, or TMZ alone. These results suggest a synergistic effect between Pam3CSK4 and TMZ based on the induction of TLR-dependent GSC differentiation towards mature GBM cells, which exhibited increased sensitivity to chemotherapy, and provide new perspectives in GBM therapy.
SN 0167-6997
YR 2020
FD 2020
LK http://riull.ull.es/xmlui/handle/915/36158
UL http://riull.ull.es/xmlui/handle/915/36158
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 22-may-2024