Abstract
Glioblastoma Multiforme (GBM), the most common and lethal adult primary tumor of the brain, showed a link between Sonic Hedgehog (SHH) pathway in the resistance to temozolomide (TMZ). PTCH1, the SHH receptor, can tonically represses signaling by endocytosis. We asked how the decrease in PTCH1 in GBM cells could lead to TMZ-resistance. TMZ resistant GBM cells have increased PTCH1 mRNA and reduced protein. Knockdown of Dicer, a Type III RNAase, indicated that miRNAs can explain the decreased PTCH1 in TMZ resistant cells. Computational studies, real-time PCR, reporter gene studies, western blots, target protector oligos and ectopic expression identified miR-9 as the target of PTCH1 in resistant GBM cells with concomitant activation of SHH signaling. MiR-9 mediated increases in the drug efflux transporters, MDR1 and ABCG2. MiR-9 was increased in the tissues from GBM patients and in an early passage GBM cell line from a patient with recurrent GBM but not from a naïve patient. Pharmacological inhibition of SHH signaling sensitized the GBM cells to TMZ. Taken together, miR-9 targets PTCH1 in GBM cells by a SHH-independent method in GBM cells for TMZ resistance. The identified pathways could lead to new strategies to target GBM with combinations of drugs.
Highlights
Gliobastoma (GBM), the most common and aggressive adult human primary brain tumor with a median survival of 11 months and 5% survival at 5 years of diagnosis
sonic hedgehog (SHH) signaling occurs with decreased PTCH1 [25]
This study investigated if TMZ resistant cells showed a decrease in PTCH1
Summary
Gliobastoma (GBM), the most common and aggressive adult human primary brain tumor with a median survival of 11 months and 5% survival at 5 years of diagnosis. The treatment for GBM includes surgery, radiotherapy and, Temozolomide (TMZ) or Bevacizumab (Avastin®) [1]. Bevacizumab, which is a humanized monoclonal antibody to vascular endothelial growth factor A, has been reported to have little improvement as compared to the standard treatment and, with a worse quality of life for the patients [2]. The cellular pathways involved in the growth and survival of GBM include phosphoinositol-3-phosphate Kinase (PI3K), mitogen activated protein kinase (MAPK), and sonic hedgehog (SHH) [3, 4]. The interaction between SHH and its 12-transmembrane Patched (PTCH1) receptor de-represses SMO, which signals through a G-protein receptor complex [8]. SHH signaling mainly occurs by the transcriptional factor, glioma-associated oncogene 1 (Gli1), which is a downstream of SMO. The over-activation of SHH signaling has been implicated in several tumors, including GBM [9]
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