Activation of autophagy in mesenchymal stem cells provides tumor stromal support

Sánchez, Cecilia G.; Penfornis, Patrice; Oskowitz, Adam Z.; Boonjindasup, Aaron; Cai, David Z.; Dhule, Santosh S.; Rowan, Brian G.; Kelekar, Ameeta; Krause, Diane S.; Pochampally, Radhika

doi:10.1093/carcin/bgr029

Cited by 97 publications

(78 citation statements)

References 35 publications

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“…Previous studies have revealed that the promotion of the expression of Beclin 1 through reduced autophagy demonstrates anticancer effects (25,26,31). The present study indicated that Beclin 1 expression levels were significantly decreased subsequent to treatment with DHA and EPA, which suggests that ω-3 PUFAs inhibit autophagosome formation in A549 cells.…”

Section: Discussionsupporting

confidence: 61%

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Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Yao

Wang

et al. 2015

Oncology Letters

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Abstract. The present study identified that ω-3 long chain polyunsaturated fatty acids (ω-3 PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrate anti-proliferative effects in lung cancer A549 cells. MTS and cytotoxicity assays were conducted to confirm that ω-3 PUFAs induced cell death. Autophagy-associated gene and signaling pathways were also detected. Microtubule-associated protein light chain 3 (LC3) expression was found to be increased subsequent to treatment with DHA and EPA, and the expression of LC3-II was particularly increased. mRFP-GFP-LC3 fluorescence staining and p62 expression levels were used to detect autophagic flux. The present results indicate that DHA and EPA block autophagic flux, suggesting autophagosome accumulation. Subsequent to treatment with DHA and EPA, which interfered with autophagosomes, the expression of Beclin 1 was significantly decreased, while the expression of phosphorylated Akt and phosphorylated mammalian target of rapamycin was significantly increased. Therefore, DHA and EPA exert anti-proliferative effects by inhibiting autophagy in A549 cells, which highlights the potential of DHA and EPA for use in the prevention or treatment of lung cancer. IntroductionLung cancer is the leading cause of cancer-associated mortality worldwide (1), and the five-year survival rate remains extremely poor (2). Overall, ~75-85% of lung cancers cases are non-small cell lung cancer (NSCLC), which includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma. The treatment of lung cancer involves the use of medical therapies such as surgery, radiation, chemotherapy and palliative care (3) in an attempt to successfully treat or reduce the adverse impact of malignant neoplasms originating in lung tissue. Chemotherapeutic agents are the main treatment measures for NSCLC, but the side-effects are usually difficult to tolerate (4).Fish oils are an excellent source of long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplements are increasingly recognized by clinical studies to be useful for the treatment of a variety of human afflictions, including cancer (5). Numerous studies reveal evidence for the capability of ω-3 PUFAs to decrease proliferation, exert a pro-apoptotic effect and inhibit angiogenesis in several in vitro models of colon cancer (6-9).A previous study indicated that DHA and EPA inhibit the proliferation of A549 cells and induce apoptosis, with autophagy also being observed under transmission electron microscopy (10). Autophagy is a type of programmed cell death and it is an important process that is involved in various human pathologies. Previous studies suggest that autophagy is important in the regulation of cancer development and progression and also in determining the response of tumor cells to anticancer therapy (11)(12)(13)(14). Several cell signaling pathways are implicated in regulating autophagy, including the phosphatidyl inositol 3-kinase (PI3K)/Akt/...

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Section: Discussionsupporting

confidence: 61%

“…During the formation of autophagosomes, the LC3-I cytoplasmic form is cleaved and lipidated to generate the membranous LC3-II form (25,26). To determine the form of LC3 that is affected by the presence of DHA and EPA, western blot analysis was used to detect LC3-I and LC3-II levels.…”

Section: Discussionmentioning

confidence: 99%

Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Yao

Wang

et al. 2015

Oncology Letters

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“…The protective effect of autophagy has been previously reported in models of ischemic injury in the heart, brain, and under conditions of H/SD in cell culture [2224]. Recently, Sanchez et al [20] reported that during long period of serum deprivation, MSCs could utilize autophagy to provide needed energy and secret anti-apoptotic factors for survival. In our research we found that autophagic pathway was activated effectively by hypoxic-preconditioning as shown by increased autophagosomes, LC3-II, and decreased A, Western blotting analysis showed that leptin-knockdown down-regulated the p-AMPK in BMSCs which was up-regulated by hypoxic-preconditioning.…”

Section: Discussionmentioning

confidence: 90%

Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis

Wang

Zhu

et al. 2014

Sci. China Life Sci.

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Autophagy is the basic catabolic progress involved in cell degradation of unnecessary or dysfunctional cellular components. It has been proven that autophagy could be utilized for cell survival under stresses. Hypoxic-preconditioning (HPC) could reduce apoptosis induced by ischemia and hypoxia/serum deprivation (H/SD) in bone marrow-derived mesenchymal stem cells (BMSCs). Previous studies have shown that both leptin signaling and autophagy activation were involved in the protection against apoptosis induced by various stress, including ischemia-reperfusion. However, it has never been fully understood how leptin was involved in the protective effects conferred by autophagy. In the present study, we demonstrated that HPC can induce autophagy in BMSCs by increased LC3-II/LC3-I ratio and autophagosome formation. Interestingly, similar effects were also observed when BMSCs were pretreated with rapamycin. The beneficial effects offered by HPC were absent when BMSCs were incubated with autophagy inhibitor, 3-methyladenine (3-MA). In addition, down-regulated leptin expression by leptin-shRNA also attenuated HPC-induced autophagy in BMSCs, which in turn was associated with increased apoptosis after exposed to sustained H/SD. Furthermore, increased AMP-activated protein kinase phosphorylation and decreased mammalian target of rapamycin phosphorylation that were observed in HPC-treated BMSCs can also be attenuated by down-regulation of leptin expression. Our data suggests that leptin has impact on HPC-induced autophagy in BMSCs which confers protection against apoptosis under H/SD, possibly through modulating both AMPK and mTOR pathway. BMSCs, autophagy, hypoxic-preconditioning, leptin, apoptosis Citation:Wang LH, Hu XY, Zhu W, Jiang Z, Zhou Y, Chen PP, Wang JA. Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis. Sci China Life Sci, 2014Sci, , 57: 171 -180, doi: 10.1007 Although severe hypoxia can lead to cell death for certain cell types such as endothelial cells, repeated episodes of short periods' exposure to hypoxia (hypoxic-preconditioning) have shown conferring cytoprotective benefits. Research done in our laboratory and others has revealed that hypoxic-preconditioning protects bone marrow-derived mesenchymal stem cells (MSCs) from apoptosis and enhances cell survival after implantation [1,2]. However, the mechanisms underlying the beneficial effects of hypoxia preconditioned MSCs remain unclear. Autophagy is the cellular process responsible for the degradation and removal of damaged organelles and protein aggregates [3]. Autophagy is critical to cell survival. The interruption of autophagy may initiate severe energy metabolism disorder and cell death [4]. Many scientists have reported that activation of autophagy protects MSCs from apoptosis [5]. Recent cancer research demonstrates that hypoxia activates autophagy and promotes tumor cell survival [6]. We hypothesized that hypoxic-preconditioning induces autophagy of bone marrow-derived MSCs (BMS...

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“…MSCs are associated with EMDR by secreting soluble molecular factors such as SDF-1, IL-6, NO, IL-3, G-CSF, M-CSF and GM-CSF and by activating proliferation pathways in tumor cells and producing ECM to protect tumor cells against chemotherapy drugs. MSCs utilize autophagy to recycle macromolecules and synthesize antiapoptotic factors to facilitate the survival and growth of surrounding tumor cells (71). In colorectal carcinoma, MSCs stimulated survival of tumor cells through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signaling cascade (72).…”

Section: Angiogenesis One Of the Effects Of Mscs On Tumor Cells Is Amentioning

confidence: 99%

Mesenchymal stem cells in the tumor microenvironment

Guan

Chen

2013

Biomedical Reports

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Abstract. Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent cells, which are able to differentiate to bone, adipose and cartilage tissue. MSCs have the characteristic of migration to injured areas or tumor microenvironment following induction by chemokines or inflammatory factors. An increasing number of studies have reported that MSCs recruited to the tumor microenvironment play various roles in tumor cell development and tumor progression. In this study, we reviewed the studies related to the tumor-promoting roles of MSCs from several aspects, such as increasing stemness of tumor cells, mediating migration, promoting angiogenesis, suppressing immune response and inducing drug resistance.

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Activation of autophagy in mesenchymal stem cells provides tumor stromal support

Cited by 97 publications

References 35 publications

Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis

Mesenchymal stem cells in the tumor microenvironment

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