Enhancement of autophagy is a potential modality for tumors refractory to radiotherapy

Kuwahara, Yoshikazu; Oikawa, T.; Ochiai, Yoshihiro; Roudkenar, Mehryar Habibi; Fukumoto, Manabu; Shimura, Tsutomu; Ohtake, Yosuke; Ohkubo, Yasuhito; Mori, Shiro; Uchiyama, Yasuo

doi:10.1038/cddis.2011.56

Cited by 85 publications

(69 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1B; P<0.01). The differentiated TAM group demonstrated the highest expression levels of CD68, CD204 and CD206 cell surface markers among the 3 groups, consistent with previous studies (15)(16)(17) (Fig. 1C).…”

Section: Induction Of Thp-1 Differentiation and The Identification Ofsupporting

confidence: 91%

“…Studies have also confirmed that TAMs secrete TGF-β, PDGF, tumor necrosis factor-α, matrix metalloproteinase-9 and other factors, to promote tumor angiogenesis and accelerate tumor growth (21,24). Previous studies have demonstrated that TAMs secrete PDGF, IL-1 and -6 to aid tumor cell survival and reduce tumor radiosensitivity (15,16,25). Thus, the study of TAMs may uncover novel methods to improve the results of radiotherapy.…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells

Shao

Zhu

Chen

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Tumor-associated macrophages (TAMs), a major component of the tumor microenvironment, are crucial to the processes of tumor growth, infiltration and metastasis, and contribute to drug resistance. The importance of TAMs in radiation resistance of colorectal cancer remains unclear. To investigate the effects of autophagy regulation of TAMs on the radiosensitivity of colorectal cancer cells, the current study induced TAM formation from THP-1 monocyte cells. Sequential treatment of THP-1 cells with PMA for 72 h and human recombinant interleukin-4 for 24 h was used to stimulate THP-1 differentiation to TAMs. Expression of the cell surface markers CD68, CD204 and CD206, and changes to cell morphology were used to confirm successful differentiation. The TAMs were stimulated to promote or inhibit autophagy during co-culture with LoVo colorectal adenocarcinoma cells. The cells were irradiated, with subsequent measurement of LoVo colony formation and apoptosis. Additionally, the expression of p53, Bcl-2, survivin and Smac proteins was assessed by western blotting. Monodansylcadaverin staining was used to analyze the presence of autophagic vacuoles in TAM, and western blot analysis was used to assess the expression of Beclin-1, LC3B I and II, ATG-3, -5 and -7. The results demonstrated TAM autophagy to be markedly altered by rapamycin and bafilomycin A1 treatment. Following co-culture with TAMs, the colony formation rate and survival fraction of LoVo cells were significantly higher than those in the control group (P<0.05). It was further demonstrated that the regulation of autophagy in TAMs was able to inhibit the colony formation of LoVo colorectal cancer cells. Upregulation of TAM autophagy using rapamycin exhibited more effective inhibition of LoVo colony formation than autophagy downregulation. Notably, apoptosis was significantly increased in LoVo cells when co-cultured with TAMs only, or with rapamycin-mediated autophagy upregulated TAMs, compared with LoVo cells cultured alone (P<0.01). Expression of Bcl-2, survivin and p53 were reduced in LoVo cells co-cultured with TAMs, compared with the control group (P<0.05), whereas Smac expression was increased in the co-culture groups (P<0.01). It was demonstrated that rapamycin-mediated autophagy stimulation in TAMs led to reduced expression levels of survivin and Bcl-2, however, Smac expression was increased. The upregulation of autophagy in TAMs inhibited proliferation and induced apoptosis in colon cancer cells, and altered the expression of radiosensitivity-associated proteins. This data indicated that the radiosensitivity of colorectal cancer cells is associated with autophagy of TAM, and that stimulating TAM autophagy may increase the radiosensitivity of colorectal cancer cells.

show abstract

Section: Induction Of Thp-1 Differentiation and The Identification Ofsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 88%

Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells

Shao

Zhu

Chen

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…298 As we identify new drugs for modulating autophagy in clinical applications, this type of information may prove useful in the identification of subgroups of patients for targeted therapy. [299][300][301] In mouse and rat tissues, endogenous LC3, ATG4B, and ATG9A have been detected by immnohistochemical analyses using both paraffin sections and cryosections. 208,[302][303][304] When autophagosomes are absent, the localization pattern of LC3 in the cells of various tissues is diffuse and cytosolic.…”

mentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

View full text Add to dashboard Cite

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

show abstract

“…mTOR plays a critical role in tumor development, invasion, and metastasis, acting as a signal integrator that modulates permissive signals from various pathways and a diversity of growth-promoting processes (5). The mTOR inhibitor rapamycin and its analogs have been shown to induce autophagy, which somewhat paradoxically is associated with its radiosensitizing effects (6)(7)(8). The mechanisms by which autophagy can mediate both radiation resistance and radiosensitivity when radiation and mTOR inhibitor are combined remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

et al. 2013

View full text Add to dashboard Cite

Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated b-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated b-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity. Cancer Res; 73(14); 4267-77. Ó2013 AACR.

show abstract

Enhancement of autophagy is a potential modality for tumors refractory to radiotherapy

Cited by 85 publications

References 39 publications

Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells

Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells

Guidelines for the use and interpretation of assays for monitoring autophagy

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

Contact Info

Product

Resources

About