ROS-Induced CXCR4 Signaling Regulates Mantle Cell Lymphoma (MCL) Cell Survival and Drug Resistance in the Bone Marrow Microenvironment via Autophagy

Abstract

Purpose Patients with advanced stages of MCL have a poor prognosis after standard therapies. MCL cells in those patients often spread into tissues other than lymph nodes, such as the bone marrow. Apart from directed migration and homing, there is little understanding of the function of the CXCR4/SDF1 signaling axis in MCL. In this report, we aim to understand mechanisms of MCL cell survival in the bone marrow. Experimental Design For comprehensive analyses of MCL interactions with bone marrow stromal cells we have generated gene knock out cells using CRISPR-CAS9 system and gene knock down cells to reveal novel roles of the CXCR4/SDF-1 signaling. Results CXCR4 silencing in MCL cells led to a significant reduction in proliferation, cell adhesion to bone marrow stromal cells and colony formation in PHA-LCM methylcellulose medium, which were reversed upon the addition of SDF-1 neutralizing antibodies. In addition, tracking MCL cell engraftment in vivo revealed that quiescent MCL cells are significantly reduced in the bone marrow upon CXCR4 silencing, indicating that CXCR4/SDF-1 signaling is required for the survival and maintenance of the quiescent MCL cells. Further analysis revealed novel mechanisms of ROS induced CXCR4/SDF-1 signaling that stimulate autophagy formation in MCL cells for their survival. Conclusions Our data, for the first time, revealed new roles of the CXCR/SDF-1 signaling axis on autophagy formation in MCL, which further promoted their survival within the bone marrow microenvironment. Targeting the CXCR4/SDF-1/autophagy signaling axis may contribute to an enhanced efficacy of current therapies.

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

“…Although autophagy acts as a "double-edged sword" in tumorigenesis (19), autophagy acts more as a cytoprotective mechanism in tumor therapy (20)(21)(22). Many anticancer agents, such as imatinib, cisplatin, vismodegib, and asparaginase, can also induce autophagy in tumor cells, whereas inhibition of autophagy significantly enhances the antitumor efficacies of these agents, indicating that a combination of autophagy inhibitors and antitumor agents could be an efficient therapeutic strategy for malignancy (23)(24)(25).…”

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

“…Reactive oxygen species (ROS) can lead to various effects on different signaling pathways and results in genomic instability by inducing DNA damage. ROS induces autophagy, which in turn functions in reducing oxidative damage [18,19], so the ROS level could be associated with chemoresistance and cancer stem cells [20,21,22]. ANE is reported to induce the ROS in both cancer cells and normal oral epithelial cells [9,23].…”

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

“…Autophagy is well-accepted as a protective mechanism for cancer cells under different conditions (17–20). In the present study, we found that silencing ATG5 led to undetectable TG2 levels and reduced NF-kB expression; while TG2 in turn regulated autophagy formation and flux.…”

“…It can be induced by different conditions, including nutrient deprivation/starvation, oxidative stress, hypoxia, and chemotherapeutic drugs (17–20). Autophagy also plays an important role in innate and adaptive immunity and can be regulated by different cytokines, such as transforming growth factor beta (TGF-β) or IL-6 (17,21–24).…”