PAK1 Mediates Bone Marrow Stromal Cell-Induced Drug Resistance in Acute Myeloid Leukemia via ERK1/2 Signaling Pathway

Li, Banban; Jia, Ruinan; Ying, Zhe; Guo, Dongmei; Teng, Qingliang; Du, Shenghong; Li, Mingying; Li, Wěi; Sun, Tao; Ma, Daoxin; Ji, Min; Ji, Chunyan

doi:10.3389/fcell.2021.686695

Cited by 9 publications

(10 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RAC3, as a GTP enzyme, has the same biological function of phosphorylating PAK1, which is similar to RAC1 in the same family 25 . Moreover, PAK1 decreased cell apoptosis and promoted chemotherapy resistance by increasing the phosphorylation of ERK1/2 in acute myeloid leukemia 26 . Therefore, we hypothesized that RAC3 affected chemosensitivity to cisplatin by regulating the phosphorylation of the PAK1‐ERK1/2 axis.…”

Section: Resultsmentioning

confidence: 99%

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

Chen

Huang

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

Cisplatin‐based chemotherapy is considered the primary treatment option for patients with advanced bladder cancer (BCa). However, the objective response rate to chemotherapy is often unsatisfactory, leading to a poor 5‐year survival rate. Furthermore, current strategies for evaluating chemotherapy response and prognosis are limited and inefficient. In this study, we aimed to address these challenges by establishing a chemotherapy response type gene (CRTG) signature consisting of 9 genes and verified the prognostic value of this signature using TCGA and GEO BCa cohorts. The risk scores based on the CRTG signature were found to be associated with advanced clinicopathological status and demonstrated favorable predictive power for chemotherapy response in the TCGA cohort. Meanwhile, tumors with high risk scores exhibited a tendency toward a “cold tumor” phenotype. These tumors showed a low abundance of T cells, CD8+ T cells and cytotoxic lymphocytes, along with a high abundance of cancer‐associated fibroblasts. Moreover, they displayed higher mRNA levels of these immune checkpoints: CD200, CD276, CD44, NRP1, PDCD1LG2 (PD‐L2), and TNFSF9. Furthermore, we developed a nomogram that integrated the CRTG signature with clinicopathologic risk factors. This nomogram proved to be a more effective tool for predicting the prognosis of BCa patients. Additionally, we identified Rac family small GTPase 3 (RAC3) as a biomarker in our model. RAC3 was found to be overexpressed in chemoresistant BCa tissues and enhance the chemotherapeutic resistance of BCa cells in vitro and in vivo by regulating the PAK1‐ERK1/2 pathway. In conclusion, our study presents a novel CRTG model for predicting chemotherapy response and prognosis in BCa. We also highlight the potential of combining chemotherapy with immunotherapy as a promising strategy for chemoresistant BCa and that RAC3 might be a latent target for therapeutic intervention.

show abstract

Section: Resultsmentioning

confidence: 99%

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

Chen

Huang

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

show abstract

“…PAK1 is an important non-receptor serine/threonine kinase that serves as a downstream activator of various oncogenic signaling pathways. [38][39][40] PAK1 expression is upregulated in PC compared to normal tissues. [41,42] The inhibition of PAK1 by inhibitor or the upstream molecule could suppress PC metastasis, PC cell proliferation and drug resistance, and immunosuppressive microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…PAK1 is an important non-receptor serine/threonine kinase that serves as a downstream activator of various oncogenic signaling pathways [38–40] . PAK1 expression is upregulated in PC compared to normal tissues [41,42] .…”

Section: Discussionmentioning

confidence: 99%

Exosomal miR-485-3p derived from pancreatic ductal epithelial cells inhibits pancreatic cancer metastasis through targeting PAK1

Zhou

Zhang

et al. 2022

Chinese Medical Journal

View full text Add to dashboard Cite

Background: Cell competition is an important feature in pancreatic cancer (PC) progression, but the underlying mechanism remains elusive. This study aims to explore the role of exosomes derived from normal pancreatic ductal epithelial cells involved in PC progression. Methods: PC cells and pancreatic stellate cells (PSCs) were treated with exosomes isolated from pancreatic ductal epithelial cells. Cell proliferation was assessed by CCK8 assays. Cell migration and invasion were assessed by Transwell assays. PC and matched adjacent non-tumor tissue specimens were obtained from 46 patients pathologically diagnosed with PC at Peking University First Hospital from 2013 to 2017. Tissue miR-485-3p and p21-activated kinase-1 (PAK1) expression was examined by real-time polymerase chain reaction (RT-PCR), and the relationship of the two was analyzed using Pearman's product-moment correlation. The clinical significance of miR-485-3p was analyzed using the Chi-square test, Wilcoxon rank-sum test, and Fisher exact probability, respectively. The binding of miR-485-3p to PAK1 5′-untranslated region (5′-UTR) was examined by luciferase assay. PC cells were xenografted into nude mice as a PC metastasis model. Results: Exosomes from pancreatic ductal epithelial cells suppressed PC cell migration and invasion as well as the secretion and migration of PSCs. MiR-485-3p was enriched in the exosomes of pancreatic ductal epithelial cells but deficient in those of PC cells and PSCs, in accordance with the lower level in PSCs and PC cells than that in pancreatic ductal cells. And the mature miR-485-3p could be delivered into these cells by the exosomes secreted by normal pancreatic duct cells, to inhibit PC cell migration and invasion. Clinical data analysis showed that miR-485-3p was significantly decreased in PC tissues (P < 0.05) and was negatively associated with lymphovascular invasion (P = 0.044). As a direct target of miR-485-3p, PAK1 was found to exert an inhibitory effect on PC cells, and there was a significantly negative correlation between the expression levels of miR-485-3p and PAK1 (r = −0.6525, P < 0.0001) in PC tissues. Moreover, miR-485-3p could suppress PC metastasis in vivo by targeting p21-activated kinase-1. Conclusions: Exosomal miR-485-3p delivered by normal pancreatic ductal epithelial cells into PC cells inhibits PC metastasis by directly targeting PAK1. The restoration of miR-485-3p by exosomes or some other vehicle might be a novel approach for PC treatment.

show abstract

“…showed that interactions between stromal‐derived factor 1α (SDF‐1α) and its cognate receptor CXCR4 promote prolonged activation of ERK and PI3K signaling pathways, leading to resistance of AML cells to apoptosis induced by chemotherapy, and protective effects of BMSCs were abrogated by pharmacological inhibition of CXCR4 206 . Other studies also revealed that BMSCs‐mediated protection of AML cells from chemotherapy involves persistent activation of Notch signaling, 195 Wnt/β‐catenin signaling, 207 and ERK1/2 signaling 208 . Notably, Chen et al.…”

Section: Drug Resistance Mechanisms In Amlmentioning

confidence: 99%

“…206 Other studies also revealed that BMSCsmediated protection of AML cells from chemotherapy involves persistent activation of Notch signaling, 195 Wnt/β-catenin signaling, 207 and ERK1/2 signaling. 208 Notably, Chen et al demonstrated that co-culturing of AML cells with human BM stromal cell line HS-5 cells resulted in upregulation of PI3K/AKT signaling, which is essential for resistance to multiple chemotherapeutic drugs including daunorubicin, homoharringtonine, and cytarabine, indicating that the BMSC-induced drug resistance mechanism is not necessarily limited by a drug's mechanism of action. 198 Similar BM stroma-mediated protective mechanisms have been observed for molecularly targeted therapy.…”

Section: Bm Stroma-mediated Resistancementioning

confidence: 99%

Acute myeloid leukemia in elderly patients: New targets, new therapies

Park

Gregory

2023

Aging and Cancer

View full text Add to dashboard Cite

Prior to the past few years, the development of new therapies for acute myeloid leukemia (AML) has been disappointingly slow. For several decades, the standard therapy for AML has consisted of intensive induction chemotherapy, and potentially a subsequent hematopoietic stem cell transplant. Unfortunately, older patients are less responsive to, and are frequently unfit to tolerate, such intensive chemotherapy. Given that a majority of AML patients are elderly, this population has been most affected by the lack of newer less toxic therapies.However, in recent years, the treatment landscape for AML has dramatically shifted with the approval of many new drugs. As summarized in this review, several of these new drugs are targeted agents that are better tolerated than standard chemotherapy and could substantially benefit elderly patients. Although drug resistance remains a major concern, the treatment options for elderly AML patients are more numerous than ever before, bringing new promise for improved patient outcomes. ACUTE MYELOID LEUKEMIAAcute myeloid leukemia (AML) comprises a heterogenous group of malignant disorders characterized by aberrant clonal expansion and accumulation of immature myeloid precursors (myeloblasts) in the bone marrow (BM), peripheral blood, and other tissues. The expansion of myeloblasts occurs at the expense of normal production of myeloid lineage cells including erythrocytes, monocytes, granulocytes, and megakaryocytes. 1 Diagnosis and clinical presentationThe median age at AML diagnosis is 67 years old, with approximately 30% of diagnosed patients above the ageThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

show abstract

PAK1 Mediates Bone Marrow Stromal Cell-Induced Drug Resistance in Acute Myeloid Leukemia via ERK1/2 Signaling Pathway

Cited by 9 publications

References 46 publications

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

Exosomal miR-485-3p derived from pancreatic ductal epithelial cells inhibits pancreatic cancer metastasis through targeting PAK1

Acute myeloid leukemia in elderly patients: New targets, new therapies

Contact Info

Product

Resources

About