Enhanced Hsa-miR-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3/5A-Addicted Glioblastoma

Abstract

Background: Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including STAT3 and STAT5A, have been indicated to play important roles in GBM progression. Increasing number of reports suggest that garcinol, a polyisoprenylated benzophenone and major bioactive component of Garcinia indica contains potent anti-cancer activities. Material and Methods: The present study investigated the anti-GBM effects of garcinol, focusing on the STAT3/STAT5A activation, using a combination of bioinformatics, in vitro, and ex vivo assays. Results: Our bioinformatics analysis of The Cancer Genome Atlas (TCGA)–GBM cohort (n = 173) showed that STAT3 and STAT5A are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort (n = 45) showed an estimated 5.3-fold (p < 0.001) elevation in STAT3 and STAT5A protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. The results were further verified in vivo using U87MG mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Conclusions: We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM.

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

“…About 50% of miRNAs are located at sites in the genome frequently amplified or deleted in cancers [64]. miR-181 glioblastoma Upregulated-caused ↓STAT, ↓migration [66] Two groups of differentially regulated miRNAs were revealed in PaCa cells treated with garcinol alone and in combination with gemcitabine [51]. Tumour suppressors were upregulated and oncogenes were downregulated by garcinol.…”

“…In cancer, the inhibition of miR-181 improves migration and may be used as an independent predictor of clinical outcomes in patients with different types of cancer. Studies on glioblastomas revealed increased miR-181 expression, decreased STAT3, and diminished vimentin after garcinol treatment [ 66 ]. In chemoresistant A549 cell lines, garcinol increased apoptosis and upregulated the miRNAs responsible for the inhibition of EMT [ 65 ].…”

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

“…The recognition and combination of ligand chemokine ligand 21 (CCL21) and C-C chemokine receptor 7 (CCR7) increase the expression of pluripotency-related transcription factors and stem cell markers (such as OCT4, CD133, CD44) by activating the JAK2/STAT3 signaling pathway, thereby enhancing the invasion, migration, and tumorsphere formation of oral squamous cell carcinoma (100). In addition, the STAT3 or STAT5A plays an important role in glioblastoma, which can be verified by the expression of OCT4 (101). The study further found that JAK/STAT3 activity is essential for DNA demethylation of Oct4 promoter during mouse somatic cell reprogramming (102,103).…”

<p>Baohuoside I via mTOR Apoptotic Signaling to Inhibit Glioma Cell Growth</p>

“… 3 Chemotherapy toxicity, side effects of radiotherapy and “multi-resistance” cannot be resolved. 4 Low toxicity, high efficiency and high selective therapy are the most attractive research areas in recent years.…”

“…Multiple signal pathways play an important role in the proliferation of glioma cells, such as the JAK2/STAT3, AMPK/mTOR and Nrf2 signaling pathways, 4 and the high activation of the mTOR signaling pathway is one of the key factors in the occurrence of glioma. 9 The purpose of this study was to investigate the effects of Baohuoside I on proliferation, migration and apoptosis of glioma cells.…”