Valproic acid inhibits cell proliferation and PD-L1-mediated tumor immune escape through targeting CIP2A and c-MYC/PI3K/Akt/mTOR signalling molecules in breast cancer
نویسندگان: Elahe Zeinali, Vahid Bagheri, Esmaeil Rostami, Gholamreza Anani Sarab ©
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Background and Aim
Resistant cells are a critical problem that reduce treatment efficacy of breast cancer. Nowadays, CIP2A and PD-L1 are considered as theraputical challenges in breast cancer, because of responsible for drug resistance and immune evasion respectively. Hence, identifying agents to suppress these factors is great of interest. Specifically, epigenetic drugs can be an effective approach to alter the behavior of genes. Although valproic acid (VPA) as a HDAC inhibitor has certain anticancer properties but molecular mechanism of VPA in breast cancer cells remains to be explored. In this study, we investigated drug effects and molecular mechanisms of VPA, particularly its effect on CIP2A and PD-L1 in breast cancer MCF-7 cell line.
In this study, MCF-7 cells were treated with various concentration of VPA for 24 h, 48 h, and 72 h. The rate of cell viability was measured by MTT assay. Finally, gene expressions of CIP2A, c-MYC, PI3K, Akt, mTOR and PD-L1 were analyzed by real time PCR and ΔCT method.
VPA showed a growth inhibitory effect in a dose and time-dependent manner in MCF-7 cell line. This effect is achieved by decreasing the expression levels of CIP2A oncogene and its downstream signaling molecules i.e. c-MYC, PI3K, Akt and mTOR. Furthermore, VPA decreased the expression levels of PD-L1 in relation to CIP2A inhibition.
These results indicated that VPA exerts its growth inhibitory effect through targeting the CIP2A and its downstream signaling molecules. In addition to being a CIP2A targeting agent, VPA also inhibits PD-L1 through CIP2A inactivation in MCF-7 cell line. Our findings suggest that VPA can be a novel approach to combat with challenges caused by CIP2A and PD-L1, thereby alone or in combination with existing therapies could be promising strategy to get more efficiencies in treatments for breast cancer patients.
Valproic acid (VPA);histone deacetylase inhibitor (HDACi); CIP2A, PD-L1; c-MYC; PI3K; Akt; mTOR; breast cancer
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