p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis

Abstract

Malignant glioma is a highly aggressive brain tumor with a poor prognosis. Chemotherapy has been observed to prolong overall survival rate and temozolomide (TMZ), a promising chemotherapeutic agent for treating glioblastoma (GBM), possesses the most effective clinical activity at present, although drug resistance limits its clinical outcome. Growing evidence supports the concept that initial and recurrent GBM may derive from glioblastoma stem cells, which may be responsible for drug resistance. However, the molecular mechanisms underlying this resistance remain to be elucidated. In the present study, a TMZ-resistant GBM cell line, U251R, was developed and subsequently divided into two subpopulations according to the CD133 immunophenotype. No significant difference was identified in the expression of O6-methylguanine-DNA-methyltransferase (MGMT) between CD133+ U251R cells and CD133− U251R cells, whereas the CD133+ cell population was more resistant to TMZ-induced growth inhibition and cell death. TMZ achieves its cytotoxic effect by inducing DNA lesions and p53 upregulated modulator of apoptosis (PUMA) is an essential mediator of DNA damage-induced apoptosis independently of p53 status. Therefore, whether PUMA effectively enhances growth suppression and induces apoptosis when combined with TMZ was investigated. Consequently, it was found that adenoviruses expressing wild-type-PUMA not only lead to the apoptosis of CD133+ U251R cells alone, but also significantly increase their sensitivity toward TMZ by elevating the Bcl-2-associated X protein/B-cell lymphoma-2 ratio without alterations in MGMT expression. Therefore, PUMA may be a suitable target for intervention to improve the therapeutic efficacy of TMZ.

4′‐Phenyl‐2,2′:6′,2′′‐terpyridine Derivatives Containing 1‐Substituted‐2,3‐Triazole Ring: Synthesis, Characterization and Anticancer Activity

“…Protein p53 is crucial tumor suppressor protein involved in DNA repair and cell death. Cancers with a mutation in this gene are often more difficult to treat with higher metastatic potency and drug resistance ,. Anticancer activity for all of the synthesized compounds was tested in vitro according to MTS procedure.…”

The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death

“…Through methylation of the O(6) position of guanine, TMZ induces DNA damage resulting in cytotoxic DNA adduct accumulation and cell apoptosis accompanied by mitochondrial dysfunction, endoplasmic reticular stress, and autophagy formation [26]. Several signaling cascade mediators have been identified to be involved in TMZ cytotoxicity, such as the Mcl-1/Bak axis [27], heat-shock proteins (MSH2, HSPA, and HSPB1) [28], and p53 [29]. However, no studies have comprehensively analyzed TMZ-mediated gene networks or miRNA signatures.…”

Phosphoribosylpyrophosphate Synthetase 1 Knockdown Suppresses Tumor Formation of Glioma CD133+ Cells Through Upregulating Cell Apoptosis

“…Recently, a substantial number of studies have implicated that CD133-positive (CD133+) cells exhibit radioresistance and chemoresistance properties, which were thought to be the source of tumor recurrence after treatment (Bao et al 2006;McCord et al 2009;Miao et al 2015). CD133+ cells isolated from glioblastoma surgical specimens or GBM cell lines were able to form invasive brain tumors in a xenograft mouse model (Hemmati et al 2003).…”