Abstract
Resistance to temozolomide (TMZ), the standard chemotherapy agent for glioblastoma (GBM), poses a major clinical challenge to GBM prognosis. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. Recent studies suggest that bioenergetic alterations of cancer cells play important roles in drug resistance. In our study, the altered metabolism of cancer cells was observed using a metabolic PCR array. We found that stearoyl-coenzyme A desaturase 1 (SCD1), a key rate-limiting enzyme for synthesis of monounsaturated fatty acids, was significantly upregulated in TMZ-resistant GBM cells compared to their parental counterparts. Overexpression of SCD1 promoted resistance to TMZ in parental GBM cells, whereas SCD1 downregulation by siRNA could re-sensitize TMZ-resistant cells in vitro. Combinational treatment of TMZ and an SCD1-specific inhibitor showed a combined inhibitory effect on TMZ-resistant glioma cells. We also observed that overexpression of SCD1 promoted Akt/GSK3β/β-catenin signaling, while silencing of SCD1 inhibited the signaling. The combination of an Akt activator with exogenous SCD1 or the combined inhibition of Akt and enforced expression of SCD1 resulted in the most significant changes of Akt signaling. Functionally, significantly lower viability and mobility rates were observed in TMZ-resistant cells when treated with Akt inhibitors and an SCD1 inhibitor simultaneously compared to when treated individually. In conclusion, our study identified SCD1 along with its functional pathway as a novel target in the development of TMZ resistance. SCD1 inhibition used alone or in combination with Akt inhibition could effectively overcome TMZ resistance in gliomas.
Highlights
Glioblastoma (GBM), the most common and lethal form of primary intrinsic brain tumors in adults, has the highest mortality rate among all malignant brain and CNS tumors
Our findings revealed that stearoyl-coenzyme A desaturase 1 (SCD1) plays a pivotal role in TMZ-resistant GBM, and that targeting SCD1 could re-sensitize TMZ-resistant GBM cells through the Akt/GSK3β/β-catenin signaling axis
(Liu et al, 2017), was examined by western blot to estimate the degree of epithelial-to-mesenchymal transition (EMT)
Summary
Glioblastoma (GBM), the most common and lethal form of primary intrinsic brain tumors in adults, has the highest mortality rate among all malignant brain and CNS tumors. Recent studies have indicated that a majority of patients with GBM gradually develop resistance to TMZ during treatment. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance (Pavlova and Thompson, 2016). LDH-A knockdown by siRNA could re-sensitize taxol-resistant breast cancer cells to taxol (Zhou et al, 2010). ATP citrate lyase, the first and rate-limiting step for de novo lipogenesis, was found to mediate SN38 resistance in colorectal cancer cells (Zhou et al, 2013). These findings suggest that targeting key metabolic enzymes could provide promising strategies for improving treatment efficacy
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