Tanshinone IIA regulates human AML cell proliferation, cell cycle, and apoptosis through miR-497-5p/AKT3 axis

Abstract

Background: The roots of Salvia miltiorrhiza are used in traditional Chinese medicine (TCM) and have high medicinal value. Tanshinone IIA (Tan IIA) is the active ingredient of Salvia miltiorrhiza which can inhibit the growth of acute leukemia cell lines in vitro, although the mechanism remains unclear. Methods: CCK-8 assays and BrdU stain were used to evaluate cell proliferation ability. Western blot analysis was used to detect protein expression. miR-497-5p expression level was detected by using qRT-PCR, and Annexin V-FITC/propidium iodide (PI) was used to detect cell apoptosis. Results: Here we reported that Tan IIA could inhibit cell proliferation, induce cell cycle arrest, and promote cell apoptosis in acute myeloid leukemia (AML) cells. Thus, Tan IIA had the anti-cancer activity in AML cell lines, which was likely mediated by up-regulation of miR-497-5p expression. Our data further showed that in AML cells, the same effects were observed with overexpression of miR-497-5p by a miR-497-5p mimic. We demonstrated that Tan IIA could inhibit the expression of AKT3 by up-regulating the expression of miR-497-5p. We subsequently identified that AKT3 was the direct target of miR-497-5p, and that treatment with Tan IIA obviously reversed the effect of treatment with an miR-497-5p inhibitor under harsh conditions. In turn, PCNA expression was increased and cleaved Caspase-3 was suppressed, which contributed to the growth of AML cells. Conclusions: Our results showed that Tan IIA could inhibit cell proliferation in AML cells through miR-497-5p-mediated AKT3 downregulation pathway.

NEDD9 overexpression: Prognostic and guidance value in acute myeloid leukaemia

“…Downregulated microRNAs such as miR-135a, miR-203, miR-497, miR-381, miR-370 and miR-758 were found to be underexpressed in AML or have anti-leukaemia effects in previous reports. [29][30][31][32][33][34][35] Of these microRNAs, miR-381 was also identified as a microRNA that could direct target NEDD9 (Figure 5E and Table S2), which suggested NEDD9 is a direct target of miR-381.…”

LncRNA CD27-AS1 promotes acute myeloid leukemia progression through the miR-224-5p/PBX3 signaling circuit

“…However, in other pathological processes, miR-224-5p has been reported to target multiple genes, including AKT3 44 , Rac1 45 , and Rab10 46 . These three factors were able to promote the growth of AML cells 47 – 49 . The findings indicate that miR-224-5p may regulate the growth of AML cells by targeting multiple genes.…”

Salvia miltiorrhiza in cancer: Potential role in regulating MicroRNAs and epigenetic enzymes

“…It has been reported that miRNAs target proliferation-related genes and proteins, such as PKM, Akt, and MEF2D, to regulate tumor cell proliferation ( Xu et al, 2020 ). Tan IIA suppresses the proliferation of AML cells (HL-60 and THP-1), glioma cells, esophageal cancer cells (EC109), breast cancer cells, and NSCLC cells through targeting miR-497-5p/Akt3, miR-122/PKM2, miR-16-5p/TLN1, miR-125b/STAR13, and let-7a-5p/aurora kinase A (AURKA), respectively ( Zhang et al, 2016 ; Liu et al, 2020a ; Liu et al, 2020 ; Nie et al, 2020 ; You et al, 2020 ; Li et al, 2022 ). Moreover, tan I, CPT, and tan IIA share common targets, including miR-137 and let-7a-5p, which function in inhibiting the proliferation of NSCLC by regulating the expression of ULK2/IBTK and AURKA, respectively; these common targets may be a result of highly similar chemical structures ( Zhang et al, 2016 ; Liu et al, 2020a ).…”