Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Drug resistance mainly drives GBM patients to poor prognoses because drug-resistant glioblastoma cells highly defend against apoptotic insults. This study was designed to evaluate the effects of cobalt chloride (CoCl2) on hypoxic stress, autophagy, and resulting apoptosis of human and mouse drug-resistant glioblastoma cells. Treatment of drug-resistant glioblastoma cells with CoCl2 increased levels of hypoxia-inducible factor- (HIF-) 1α and triggered hypoxic stress. In parallel, the CoCl2-induced hypoxia decreased mitochondrial ATP synthesis, cell proliferation, and survival in chemoresistant glioblastoma cells. Interestingly, CoCl2 elevated the ratio of light chain (LC)3-II over LC3-I in TMZ-resistant glioblastoma cells and subsequently induced cell autophagy. Analyses by loss- and gain-of-function strategies further confirmed the effects of the CoCl2-induced hypoxia on autophagy of drug-resistant glioblastoma cells. Furthermore, knocking down HIF-1α concurrently lessened CoCl2-induced cell autophagy. As to the mechanisms, the CoCl2-induced hypoxia decreased levels of phosphoinositide 3-kinase (PI3K) and successive phosphorylations of AKT and mammalian target of rapamycin (mTOR) in TMZ-resistant glioblastoma cells. Interestingly, long-term exposure of human chemoresistant glioblastoma cells to CoCl2 sequentially triggered activation of caspases-3 and -6, DNA fragmentation, and cell apoptosis. However, pretreatment with 3-methyladenine, an inhibitor of autophagy, significantly attenuated the CoCl2-induced autophagy and subsequent apoptotic insults. Taken together, this study showed that long-term treatment with CoCl2 can induce hypoxia and subsequent autophagic apoptosis of drug-resistant glioblastoma cells via targeting the PI3K-AKT-mTOR pathway. Thus, combined with traditional prescriptions, CoCl2-induced autophagic apoptosis can be clinically applied as a de novo strategy for therapy of drug-resistant GBM patients.
Highlights
Glioblastoma multiforme (GBM) is the most malignant brain tumor
Residual glioblastoma cells existing on the periphery of a brain tumor can speedily proliferate and invade other areas to recur as moreaggressive brain tumors [4]
Human and mouse glioblastoma cells that were resistant to TMZ treatment were prepared from their respective drug-sensitive brain tumor cells (Figure 1)
Summary
Glioblastoma multiforme (GBM) is the most malignant brain tumor. GBM patients are regularly cured with standard surgical resection and successive concurrent chemoradiotherapy [1]. Temozolomide (TMZ) is the first-line chemotherapeutic drug for GBM [2]. More than 50% of GBM patients will exhibit drug. Because GBM develops in the brain, this cerebral location limits neurosurgeons’ performance of completely removing tumors [4]. Glioblastoma cells possess unique features of rapid proliferation, migration, and invasion [5]. Residual glioblastoma cells existing on the periphery of a brain tumor can speedily proliferate and invade other areas to recur as moreaggressive brain tumors [4]. Establishing de novo strategies to overwhelm drug tolerance by GBM is an emergent and necessary issue
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