Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway

Veirman, Kim De; Menu, Eline; Maes, Ken; Beule, Nathan De; Smedt, Eva De; Maes, Anke; Vlummens, Philip; Fostier, Karel; Kassambara, Alboukadel; Moreaux, Jérôme; Ginderachter, Jo A. Van; Bruyne, Elke De; Vanderkerken, Karin; Valckenborgh, Els Van

doi:10.1016/j.canlet.2018.11.002

Cited by 50 publications

(42 citation statements)

References 43 publications

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“…Indeed, previous reports described the role of AMPK in the activation of immunosuppressive phenotypes in macrophages and in the restriction of effector T-cell expansion in tumors (12,38). In contrast to our argument that AMPK drives the tolerogenic actions of MDSC, treatment of tumor-bearing mice with the AMPK agonists Metformin, Phenformin, or OSU-53 exerted anti-tumor activities that correlated with a lower immunosuppressive function of MDSC (19)(20)(21)(22)(23)(24)(25). Conversely, additional studies showed that treatment of M-MDSC with Metformin promoted their immunosuppressive activity in allogeneic skin grafts (26); and enhanced MDSC response to the immunoinhibitory factor prostaglandin E 2 in models of doxorubicin-resistant tumors (27).…”

Section: Discussioncontrasting

confidence: 80%

“…Although the role of AMPK is well established in cancer cells, the intrinsic effect of AMPK in the modulation of MDSC in tumors remains controversial. Initial reports showed that pharmacological activation of AMPK blocked MDSC function in tumors (19)(20)(21)(22)(23)(24)(25), while additional investigations indicated that AMPK promoted MDSC activity (26)(27)(28). Development of conditional AMPK-deficient models will enable precise elucidation of the actions of AMPK signaling in tumor-associated MDSC.…”

Section: Introductionmentioning

confidence: 99%

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AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells

et al. 2019

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Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment (TME) and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumorbearing mice and ovarian cancer patients. Transcription of the Ampkα1-coding gene, Prkaa1, in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat-5-dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered anti-tumor CD8 + T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages, and rerouted M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2 (Nos2)-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-*

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Section: Discussioncontrasting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells

et al. 2019

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“…Upon activation, AMPK induces a series of metabolic changes to maintain the production of intracellular energy and balance consumption (Kurumbail and Calabrese, 2016). Recent studies have shown that AMPK is a possible autophagy-associated tumor suppressor for the prevention and treatment of several cancer types (Han et al, 2018;De Veirman et al, 2019). Accordingly, AMPK activators have been discovered as potential targeted drugs for the treatment of human cancer, and there is a need to develop novel AMPK activators with a low toxicity and high efficiency for inducing tumor cell autophagic suicide.…”

Section: Introductionmentioning

confidence: 99%

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Wang

et al. 2020

Front. Pharmacol.

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Ethoxysanguinarine (Eth) is a benzophenanthridine alkaloid extracted from Macleaya cordata (Willd) R. Br. It possesses antibacterial and antiviral activities and offers therapeutic benefits for the treatment of respiratory syndrome virus-induced cytopathic effects. However, the effect of Eth on human tumors and its pharmacological effects remain to be elucidated, together with its cellular target. Here, we examined the effects of Eth on breast cancer (BC) cells. We found that at low doses, Eth strongly inhibited the viability of BC cell lines and induced autophagy. Mechanistic studies showed that Eth induced autophagy by upregulating the activity of the AMP-activated protein kinase (AMPK). The AMPK inhibitor compound C significantly attenuated Eth-induced autophagy and inhibited proliferation. Meanwhile, the AMPK activator metformin significantly enhanced Eth-induced autophagy and inhibited proliferation. Computational docking and affinity assays showed that Eth directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. AMPK was less activated in tumor samples compared to normal breast tissues and was inversely associated with the prognosis of the patients. Moreover, Eth exhibited potent anti-BC activity in nude mice and favorable pharmacokinetics in rats. These characteristics render Eth as a promising candidate drug for further development and for designing new effective AMPK activators.

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“…In line with these observations, it was reported that high expression of LC3 or BECN1 is associated with a favorable outcome in multiple myeloma (31). Nevertheless, other studies have demonstrated an opposite role for the autophagy machinery in disease malignancy development, showing that autophagy activation is required to induce multiple myeloma cell survival (32,33). Moreover, autophagy machinery activation has been shown to be involved in the progression of other hematopoietic cancers.…”

Section: Discussionmentioning

confidence: 69%

Increased Expression of Autophagy Protein LC3 in Two Patients With Progressing Chronic Lymphocytic Leukemia

et al. 2020

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Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the western hemisphere. It is characterized by a clonal proliferation of a population of CD5+ B lymphocytes that accumulate in the secondary lymphoid tissues, bone marrow, and blood. Some CLL patients remain free of symptoms for decades, whereas others rapidly become symptomatic or develop high-risk disease. Studying autophagy, which may modulate key protein expression and cell survival, may be important to the search for novel prognostic factors and molecules. Here, we applied flow cytometry technology to simultaneously detect autophagy protein LC3B with classical phenotypical markers used for the identification of tumoral CLL B cell clones. We found that two patients with progressing CLL showed increased expression of the autophagy protein LC3B, in addition to positive expression of CD38 and ZAP70 and unmutated status of IGHV. Our data suggest that activation of autophagy flux may correlate with CLL progression even before Ibrutinib treatment.

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Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway

Cited by 50 publications

References 43 publications

AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells

AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Increased Expression of Autophagy Protein LC3 in Two Patients With Progressing Chronic Lymphocytic Leukemia

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