PTEN is indispensable for cells to respond to MAPK inhibitors in myeloid leukemia

Zhang, Jingliao; Zhang, Xiang; Malaviarachchi, Priyangi A.; Yan, Yan; Baltz, Nicholas J; Emanuel, Peter D.; Liu, Y. Lucy

doi:10.1016/j.cellsig.2018.06.004

Cited by 6 publications

(8 citation statements)

References 45 publications

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“…Our results showed that treatment with LY294002 or PD98059 but not with BIRB796 or CP690550 could significantly inhibit the effect of HPCs on MDA-MB-435s-HM cells. It is well known that the PI3K/AKT and MEK/ERK pathways play important roles in regulating cancer cell invasion or migration (Chang et al 2018 ; Bollaert et al 2018 ; Zhang et al 2018b ; Shults et al 2018 ; Yan et al 2018 ; Johnsen et al 2018 ). The Jak/STAT and p38 MAPK pathways mainly regulate the cellular stress response, immune processes, and inflammation (O’Reilly et al 2018 ; Ajibade et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells

Meng

Luo

et al. 2018

J Cancer Res Clin Oncol

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The pre-metastatic niche has been shown to play a critical role in tumor metastasis, and its formation is closely related to the tumor microenvironment. However, the underlying molecular mechanisms remain unclear. In the present study, we successfully established a mouse model of lung metastasis using luciferase-expressing MDA-MB-435s cells. In this model, recruitment of vascular endothelial growth factor receptor-1 (VEGFR1) + CD133 + hematopoietic progenitor cells (HPCs) was gradually increased in lung but gradually decreased after the formation of tumor colonies in lung. We also established a highly metastatic MDA-MB-435s (MDA-MB-435s-HM) cell line from the mouse model. Changes in protein profiles in different culture conditions were investigated by protein microarray analysis. The levels of CXC chemokine ligand 16, interleukin (IL)-2Rα, IL-2Rγ, matrix metalloproteinase (MMP)-1, MMP-9, platelet-derived growth factor receptor (PDGFR)-α, stromal cell-derived factor (SDF)-1α, transforming growth factor (TGF)-β, platelet endothelial cell adhesion molecule (PECAM)-1 and vascular endothelial (VE)-cadherin were significantly greater (> fivefold) in the culture medium from MDA-MB-435s-HM cells than in that from MDA-MB-435s cells. Moreover, the levels of MMP-9, PDGFR-α, and PECAM-1 were significantly greater in the co-culture medium of MDA-MB-435s-HM cells and CD133 + HPCs than in that from MDA-MB-435s-HM cells. Differentially expressed proteins were validated by enzyme-linked immunosorbent assay, and expression of their transcripts was confirmed by quantitative real-time polymerase chain reaction. Moreover, inhibition of MMP-9, PDGFR-α, and PECAM-1 by their specific inhibitors or antibodies significantly decreased cell migration, delayed lung metastasis, and decreased recruitment of VEGFR1 + CD133 + HPCs into lung. Intra-hepatic growth of HPCs enhanced the invasive growth of MDA-MB-435s-HM cells in the liver. Our data indicate that VEGFR1 + CD133 + HPCs contribute to lung metastasis. Electronic supplementary material The online version of this article (10.1007/s00432-018-2802-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells

Meng

Luo

et al. 2018

J Cancer Res Clin Oncol

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“…The PTEN mutational status affects the response to combined therapy based on MEK and mTOR inhibitors in cancer [37], a fact that needs to be further investigated in the context of personalized treatment. PTEN proved to be a vital factor for promoting the response to MAPK inhibitors in myeloid leukemia, as PTEN regulates EGR1 expression and contributes to the cytokine sensitivity when treated with MAPK inhibitors [38]. PTEN loss and activation of KRAS (Kirsten rat sarcoma viral oncogene homolog) are correlated with cytoskeleton alteration, and they act as possible therapeutic targets which would allow testing of new compounds for more specific targeted therapies, having the capacity to modulate the PI3K and RAS/MAPK pathways [39].…”

Section: Mapk-signaling Crosstalk and Pathologic Deregulations In mentioning

confidence: 99%

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Braicu

Buse

Busuioc

et al. 2019

Cancers

647

444

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The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.

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“…GRP78, CHOP, XBP‐1, and GRP94 are the biomarkers of ERS, and high expression of them indicates the activation of ERS (Zhang et al, ). Thus, RT‐qPCR (Figure c), Western blot analysis (Figure d) were conducted to determine GRP78, CHOP, XBP‐1, and GRP94 expression.…”

Section: Resultsmentioning

confidence: 99%

“…The study further revealed that overexpression of PTEN inhibited the MAPK signaling. Loss of PTEN contributes to the blockade of MAPK signaling, resulting in tumorigenesis (Zhang et al, ). The MAPK signaling activation was induced by intracellular stress signals in the atherosclerotic lesions (Rajamaki et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…When cell confluence reached about 50%, the cultured HAECs were transfected with miR‐103 inhibitor or mimic, and PTEN‐vector and their controls (inhibitor‐NC, mimic‐NC, and vector‐NC) using Lipofectamine 2000 (Invitrogen Inc., Carlsbad, CA). To disrupt the MAPK signaling in cells expressing miR‐103 or PTEN, the cells were further treated with MAPK inhibitor, PD98059 (100 uM; Calbiochem, La Jolla, CA; Zhang et al, ), with dimethyl sulphoxide (DMSO; 100 uM; Sigma–Aldrich Chemical Company, St Louis, MO) as control. The HAECs were treated with 50 ug/ml ox‐LDL (Beijing Xiesheng BioTechnology Limited, Beijing, China) for 24 hr, and HAECs without any treatment were used as control (F. P. Li et al, ).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of microRNA‐103 attenuates inflammation and endoplasmic reticulum stress in atherosclerosis through disrupting the PTEN‐mediated MAPK signaling

Jiang

Qiao

Wang

et al. 2019

Journal Cellular Physiology

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Atherosclerosis (AS), a chronic disorder of large arteries, is the underlying pathological process of heart disease and stroke. Former researchers have found that microRNAs (miRs) are involved in the several key processes of AS. Apolipoprotein E knockout (ApoE −/− ) mice fed a high-fat-diet (HFD) to establish AS model. The expression of miR-103 was characterized in the mice model. The effects of miR-103 on inflammation and endoplasmic reticulum stress (ERS) were analyzed when the expression of miR-103 was inhibited in ApoE −/− mice fed an HFD and human aortic endothelial cells (HAECs) exposed to oxidized low-density lipoprotein (ox-LDL). The relationship between miR-103 and phosphatase and tensin homolog (PTEN) was identified by luciferase activity detection and real-time quantitative polymerase chain reaction (RT-qPCR). Gain-and loss-function approaches were further applied for investigating the regulatory effects of miR-103 and PTEN on ERS. Role of MAPK signaling was then analyzed using PD98059 to block this pathway. miR-103 was highly expressed in the ApoEApoE −/− mice fed an HFD. Downregulation of miR-103 suppressed inflammation and ERS in endothelial cells isolated from ApoE −/− mice fed a HFD and ox-LDL-exposed HAECs. In addition, miR-103 can target PTEN and downregulate its expression. Overexpression of PTEN reversed the miR-103-induced activation of MAPK signaling. Moreover, PTEN upregulation or MAPK signaling inhibition ease miR-103-induced inflammation and ERS in vivo and in vitro. Thus, miR-103 depletion restrains the progression of AS through blocking PTEN-mediated MAPK signaling.

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PTEN is indispensable for cells to respond to MAPK inhibitors in myeloid leukemia

Cited by 6 publications

References 45 publications

Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells

Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Inhibition of microRNA‐103 attenuates inflammation and endoplasmic reticulum stress in atherosclerosis through disrupting the PTEN‐mediated MAPK signaling

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