AKR1C3 decreased CML sensitivity to Imatinib in bone marrow microenvironment via dysregulation of miR-379-5p

Pan, Di; Yang, Wanwan; Zeng, Yao; Li, Wenjun; Wang, Kaizhen; Zhao, Li; Li, Jia; Ye, Yuting; Guo, Qinglong

doi:10.1016/j.cellsig.2021.110038

Cited by 5 publications

(5 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, a CCK-8 assay and cell cycle analysis were performed to evaluate BMSC proliferation. The CCK-8 assay is mainly used to test cell proliferation and is highly sensitive [ 33 ]. A cell cycle analysis is commonly used to evaluate adherent or suspended cells, and the numbers of cells in G1, S, and G2 phases are measured using flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

SDF-1α promotes subchondral bone sclerosis and aggravates osteoarthritis by regulating the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells

Meng

Xin

Fan

2023

BMC Musculoskelet Disord

View full text Add to dashboard Cite

Background Subchondral bone sclerosis is a major feature of osteoarthritis (OA), and bone marrow mesenchymal stem cells (BMSCs) are presumed to play an important role in subchondral bone sclerosis. Accumulating evidence has shown that stromal cell-derived factor-1α (SDF-1α) plays a key role in bone metabolism-related diseases, but its role in OA pathogenesis remains largely unknown. The purpose of this study was to explore the role of SDF-1α expressed on BMSCs in subchondral bone sclerosis in an OA model. Methods In the present study, C57BL/6J mice were divided into the following three groups: the sham control, destabilization of the medial meniscus (DMM), and AMD3100-treated DMM (DMM + AMD3100) groups. The mice were sacrificed after 2 or 8 weeks, and samples were collected for histological and immunohistochemical analyses. OA severity was assessed by performing hematoxylin and eosin (HE) and safranin O-fast green staining. SDF-1α expression in the OA model was measured using an enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (q-PCR), and immunohistochemistry. Micro-CT was used to observe changes in subchondral bone in the OA model. CD44, CD90, RUNX2, and OCN expression in subchondral bone were measured using q-PCR and immunohistochemistry. In vitro, BMSCs were transfected with a recombinant lentivirus expressing SDF-1α, an empty vector (EV), or siRNA-SDF-1α. Western blot analysis, q-PCR, and immunofluorescence staining were used to confirm the successful transfection of BMSCs. The effect of SDF-1α on BMSC proliferation was evaluated by performing a CCK-8 assay and cell cycle analysis. The effect of SDF-1α on the osteogenic differentiation of BMSCs was assessed by performing alkaline phosphatase (ALP) and alizarin red S (ARS) staining. Cyclin D1, RUNX2 and OCN expression were measured using Western blot analysis, q-PCR, and immunofluorescence staining. Results SDF-1α expression in the DMM-induced OA model increased. In the DMM + AMD3100 group, subchondral bone sclerosis was alleviated, OA was effectively relieved, and CD44, CD90, RUNX2, and OCN expression in subchondral bone was decreased. In vitro, high levels of SDF-1α promoted BMSC proliferation and increased osteogenic differentiation. Cyclin D1, RUNX2, and OCN expression increased. Conclusion The results of this study reveal a new molecular mechanism underlying the pathogenesis of OA. The targeted regulation of SDF-1α may be clinically effective in suppressing OA progression.

show abstract

Section: Discussionmentioning

confidence: 99%

SDF-1α promotes subchondral bone sclerosis and aggravates osteoarthritis by regulating the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells

Meng

Xin

Fan

2023

BMC Musculoskelet Disord

View full text Add to dashboard Cite

show abstract

“…Data shows that AKR1C3 is highly up-regulated in the resistant CML BMM, and when ectopically expressed, it decreased the efficacy of IM treatment in vitro [ 81 ]. Increases in AKR1C3 were sufficient to stimulate increased MAPK/ERK signaling.…”

Section: The Role Of Mirnas In CMLmentioning

confidence: 99%

“…Conversely, miR-379-5p is downregulated in the BMM of CML but is capable of binding to AKR1C3 mRNA to suppress its translation. However, a recovery of miR-379-5p was sufficient to rescue the efficacy of IM by counteracting the increased AKR1C3 [ 81 ]. Similarly, miR-221 is decreased in mononuclear cells of peripheral blood taken from IM resistant compared to treatment sensitive CML patients [ 82 ].…”

Section: The Role Of Mirnas In CMLmentioning

confidence: 99%

Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance

Rudich

Garzon

Dorrance

2022

IJMS

View full text Add to dashboard Cite

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated by the presence of the fusion gene BCR::ABL1. The development of tyrosine kinase inhibitors (TKIs) highly specific to p210BCR-ABL1, the constitutively active tyrosine kinase encoded by BCR::ABL1, has greatly improved the prognosis for CML patients. Now, the survival rate of CML nearly parallels that of age matched controls. However, therapy resistance remains a persistent problem in the pursuit of a cure. TKI resistance can be attributed to both BCR::ABL1 dependent and independent mechanisms. Recently, the role of non-coding RNAs (ncRNAs) has been increasingly explored due to their frequent dysregulation in a variety of malignancies. Specifically, microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) have been shown to contribute to the development and progression of therapy resistance in CML. Since each ncRNA exhibits multiple functions and is capable of controlling gene expression, they exert their effect on CML resistance through a diverse set of mechanisms and pathways. In most cases ncRNAs with tumor suppressing functions are silenced in CML, while those with oncogenic properties are overexpressed. Here, we discuss the relevance of many aberrantly expressed ncRNAs and their effect on therapy resistance in CML.

show abstract

“…Dysregulated AKR1C3 expression is associated with the development and poor prognosis of a variety of cancers; overexpression of AKR1C3 is also related to the resistance to radiotherapy and chemotherapy in many tumor cells. , AKR1C3 mediates the development of cancer cells’ resistance to anticancer drugs such as anthracyclines in the treatment of breast cancer and acute myeloid leukemia (AML), and enzalutamide and abiraterone acetate in the treatment of castration-resistant prostate cancer (CRPC). In addition, AKR1C3 is also involved in the development of colon cancer cells’ and breast cancer cells’ resistance to cisplatin and chronic myeloid leukemia cells’ resistance to imatinib . Thus, AKR1C3 has been recognized as not only a potential diagnostic or prognostic marker but also a novel therapeutic target for overcoming chemoresistance in cancer therapy.…”

mentioning

confidence: 96%

“…In addition, AKR1C3 is also involved in the development of colon cancer cells' and breast cancer cells' resistance to cisplatin 9 and chronic myeloid leukemia cells' resistance to imatinib. 10 Thus, AKR1C3 has been recognized as not only a potential diagnostic or prognostic marker but also a novel therapeutic target for overcoming chemoresistance in cancer therapy. The effectiveness of AKR1C3-selective inhibitors combined with chemotherapeutic drugs has been confirmed in colon cancer cells, 11 liver cancer cells, 12 AML cell lines, 13 and prostate cancer cells.…”

mentioning

confidence: 99%

Discovery of Novel Aldo-Keto Reductase 1C3 Inhibitors as Chemotherapeutic Potentiators for Cancer Drug Resistance

Liu

Chu

et al. 2022

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

As a crucial target which is overexpressed in a variety of cancers, aldo-keto reductase 1C3 (AKR1C3) confers chemotherapeutic resistance to many clinical agents. However, a limited number of AKR1C3-selective inhibitors are applied clinically, which indicates the importance of identifying active compounds. Herein, we report the discovery, synthesis, and evaluation of novel and potent AKR1C3 inhibitors with structural diversity. Molecular dynamics simulations of these active compounds provide reasonable clarification of the interpreted biological data. Moreover, we demonstrate that AKR1C3 inhibitors have the potential to be superior therapeutic agents for re-sensitizing drug-resistant cell lines to chemotherapy, especially the pan-AKR1C inhibitor S07-2010. Our study identifies new structural classes of AKR1C3 inhibitors and enriches the structural diversity, which facilitates the future rational design of inhibitors and structural optimization. Moreover, these compounds may serve as promising therapeutic adjuvants toward new therapeutics for countering drug resistance.

show abstract

AKR1C3 decreased CML sensitivity to Imatinib in bone marrow microenvironment via dysregulation of miR-379-5p

Cited by 5 publications

References 28 publications

SDF-1α promotes subchondral bone sclerosis and aggravates osteoarthritis by regulating the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells

SDF-1α promotes subchondral bone sclerosis and aggravates osteoarthritis by regulating the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells

Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance

Discovery of Novel Aldo-Keto Reductase 1C3 Inhibitors as Chemotherapeutic Potentiators for Cancer Drug Resistance

Contact Info

Product

Resources

About