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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1190-1201 |
| Number of pages | 12 |
| Journal | Oncotarget |
| Volume | 6 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 1 2015 |
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All Science Journal Classification (ASJC) codes
- Oncology
Keywords
- Glioblastoma
- MicroRNA-9
- P-gp
- PTCH
- Temozolomide
Cite this
}
Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level. / Munoz, Jessian L.; Rodriguez-Cruz, Vivian; Ramkissoon, Shakti H.; Ligon, Keith L.; Greco, Steven J.; Rameshwar, Pranela.
In: Oncotarget, Vol. 6, No. 2, 01.01.2015, p. 1190-1201.Research output: Contribution to journal › Article
TY - JOUR
T1 - Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level
AU - Munoz, Jessian L.
AU - Rodriguez-Cruz, Vivian
AU - Ramkissoon, Shakti H.
AU - Ligon, Keith L.
AU - Greco, Steven J.
AU - Rameshwar, Pranela
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - Glioblastoma
KW - MicroRNA-9
KW - P-gp
KW - PTCH
KW - Temozolomide
UR - http://www.scopus.com/inward/record.url?scp=84921824931&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921824931&partnerID=8YFLogxK
U2 - https://doi.org/10.18632/oncotarget.2778
DO - https://doi.org/10.18632/oncotarget.2778
M3 - Article
C2 - 25595896
VL - 6
SP - 1190
EP - 1201
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 2
ER -