Hedgehog inhibitors selectively target cell migration and adhesion of mantle cell lymphoma in bone marrow microenvironment

Zhang, Han; Chen, Zheng; Neelapu, Sattva S.; Romaguera, Jorge; McCarty, Nami

doi:10.18632/oncotarget.7320

Cited by 24 publications

(27 citation statements)

References 55 publications

(66 reference statements)

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“…Although the mechanisms and signaling pathways of this tumorigenic event in MCL are poorly understood, [13][14][15] promising therapeutic approaches that disrupt crosstalk between the microenvironment and tumor cells to prevent the development of drug resistance and chemotherapy refractoriness are currently in early clinical development in patients with MCL. [16][17][18][19][20][21] In this study, we searched for potential SOX11 direct target genes that may explain the relationship between SOX11 and tumor microenvironment protective interactions to find new…”

Section: Introductionmentioning

confidence: 99%

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

Balsas

Palomero

Eguileor

et al. 2017

Blood

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SOX11 overexpression in mantle cell lymphoma (MCL) has been associated with more aggressive behavior and worse outcome. However, SOX11 oncogenic pathways driving MCL tumor progression are poorly understood. Here, we demonstrate that SOX11 binds to regulatory regions of 2 important genes for microenvironment signals in cancer: (C-X-C motif) chemokine receptor 4 () and (encoding for focal adhesion kinase [FAK]). Moreover, SOX11 xenograft and human primary MCL tumors overexpress cell migration and stromal stimulation gene signatures compared with their SOX11 counterparts. We show that SOX11 directly upregulates CXCR4 and FAK expression, activating PI3K/AKT and ERK1/2 FAK-downstream pathways in MCL. Concordantly, SOX11 MCL cells have higher cell migration, transmigration through endothelial cells, adhesion to stromal cells, and cell proliferation and display an increased resistance to conventional drug therapies compared with SOX11 MCL cells. Specific FAK inhibition blocks downstream PI3K/AKT- and ERK1/2-mediated phosphorylation. Additionally, specific FAK and PI3K inhibitors reduce SOX11-enhanced MCL cell migration and stromal interactions and revert cell adhesion-mediated drug resistance (CAM-DR) to the same levels as SOX11 MCL cells. In intravenous MCL xenograft models, SOX11 MCL cells display higher cell migration, invasion, and growth compared with SOX11-knockdown cells, and specific FAK and CXCR4 inhibitors impair SOX11-enhanced MCL engraftment in bone marrow. Overall, our results suggest that SOX11 promotes MCL homing and invasion and increases CAM-DR through the direct regulation of CXCR4 and FAK expression and FAK/PI3K/AKT pathway activation, contributing to a more aggressive phenotype. Inhibition of this pathway may represent an efficient strategy to overcome stromal-mediated chemotherapy refractoriness in aggressive MCL.

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Section: Introductionmentioning

confidence: 99%

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

Balsas

Palomero

Eguileor

et al. 2017

Blood

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“…Numerous studies (18–20) have described the use of pharmacological agents to demonstrate the involvement of autophagy in the regulation of cell proliferation. 3-MA, which inhibits autophagosomal cargo-sequestration and CQ, which acts on lysosmal function were used to inhibit individual steps of the autophagic pathway.…”

Section: Resultsmentioning

confidence: 99%

Autophagy is involved in aldosterone-induced mesangial cell proliferation

Wang

Miao

et al. 2016

Molecular Medicine Reports

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The aim of the present study was to investigate whether autophagy is involved in aldosterone (Aldo)-induced mesangial cell (MC) proliferation. MCs were incubated with 10−7 M Aldo for 24 h. Proliferation of MCs, and the underlying mechanisms, were subsequently analyzed using [3H]thymidine assay, cell counting assay, western blotting and RNA interference (RNAi). Aldo was revealed to induce autophagy, as indicated by the increased conversion from microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II, the increased expression levels of autophagy-related gene 7 (Atg7) and the increased degradation of p62, which was accompanied by MC proliferation. Notably, pharmacological inhibition of autophagy or RNAi-mediated knockdown of Atg7 attenuated Aldo-induced MC proliferation, suggesting that autophagy was at least partially responsible for this effect. The results of the present study provided evidence that autophagy is critical for regulating Aldo-induced MC proliferation.

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“…Cytotoxicity was assessed with fluorimetric cell viability assay using CellTiter-Blue® as previously described (27). The Hill-Slope logistic model is used to calculate IC 50 using CompuSyn software.…”

Section: Methodsmentioning

confidence: 99%

“…Procedures for qRT-PCR were performed as previously described (27). The involved primers are provided in supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

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TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

et al. 2016

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Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-kB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-kB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the present study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL-6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL-6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-kB/IL-6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-kB and IL-6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy.

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Hedgehog inhibitors selectively target cell migration and adhesion of mantle cell lymphoma in bone marrow microenvironment

Cited by 24 publications

References 55 publications

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

Autophagy is involved in aldosterone-induced mesangial cell proliferation

TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

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