Dual functions of autophagy in the response of breast tumor cells to radiation

Bristol, Molly L.; Di, Xu; Beckman, Matthew J.; Wilson, Eden N.; Henderson, Scott C.; Maiti, Aparna; Fan, Zhen; Gewirtz, David A.

doi:10.4161/auto.19313

Cited by 119 publications

(55 citation statements)

References 48 publications

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“…Figure 4C confirms that recovery occurs after radiation-induced autophagy and senescence in both the HCT116 Ligase IV-proficient and Ligase IV-deficient cells. These findings are consistent with studies where proliferative recovery was observed after irradiation of MCF-7 breast tumor cells [16, 44]. …”

Section: Resultssupporting

confidence: 93%

“…We and others have reported that a primary response of tumor cells to radiation is autophagy [44–47]. Figures 2A presents images of irradiated cells stained with acridine orange, which is indicative of autophagy while Figures 2B provides quantification of the extent of autophagy over a range of radiation doses.…”

Section: Resultsmentioning

confidence: 99%

“…We have shown proliferative recovery after induction of senescence by radiation as well as doxorubicin in breast tumor cells [16, 31, 44, 47]. The HCT116 Ligase IV proficient and HCT116 Ligase IV deficient cells were exposed to radiation doses of 6 Gy and 3 Gy, respectively; cells were sorted based on staining with the senescence marker, C 12 FDG, 96 hours post-radiation by flow cytometry (Figure 4A and Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

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Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

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Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair proficient HCT116 colon carcinoma cells and a repair deficient Ligase IV (−/−) isogenic cell line. Irradiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines; however inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Irradiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the Ligase IV (−/−) cells; however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors (Olaparib) and (Niraparib) increased the extent of persistent DNA damage induced by radiation as well as the extent of both autophagy and senescence; neither cell line underwent significant apoptosis by radiation alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiation sensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10–20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

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“…Our data revealed that calcitriol in combination with irradiation demonstrated an additive effect on the suppression of TIC-initiated spheroid formation, suggesting that these therapies likely target different pathways and provide a rationale for considering combining the two agents in clinical trials. Our findings are in agreement with previous reports documenting a sensitizing or additive effect of calcitriol with ionizing radiation (47–49). It will be interesting to further explore the molecular effects of combined treatment with calcitriol and radiation and whether calcitriol can also enhance the anti-TIC effects of chemotherapy.…”

Section: Discussionsupporting

confidence: 94%

Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D

Jeong

Swami

Krishnan

et al. 2015

Molecular Cancer Therapeutics

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The anti-cancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and pre-clinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors (VDRs) and estrogen receptors (ERs) and exhibited calcitriol-induced molecular responses including ER down-regulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth while a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies will enhance anti-cancer activity and may improve therapeutic outcomes.

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“…(1, 4, 40) Although numerous studies have shown a significant decrease in cell number with autophagy inhibition in combination with radiation or chemotherapy in breast cancer cell lines (41, 42) and in tumor xenografts;(43–45) other studies show a limited or null effect. (46) While it makes sense that autophagy inhibition may be more beneficial when used with particular cancer therapies (e.g.…”

Section: Discussionmentioning

confidence: 99%

STAT3-Mediated Autophagy Dependence Identifies Subtypes of Breast Cancer Where Autophagy Inhibition Can Be Efficacious

et al. 2014

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Autophagy is a protein and organelle degradation pathway that is involved in diverse diseases including cancer. Recent evidence suggests that autophagy is a cell survival mechanism in tumor cells and that its inhibition especially in combination with other therapy could be beneficial but it remains unclear if all cancer cells behave the same way when autophagy is inhibited. We inhibited autophagy in a panel of breast cancer cell lines and found that some of them are dependent on autophagy for survival even in nutrient rich conditions without any additional stress while others need autophagy only when stressed. Survival under unstressed conditions is due to cell type specific autophagy regulation of STAT3 activity and this phenotype is enriched in triple negative cell lines. This autophagy-dependency affects response to therapy because autophagy inhibition reduced tumor growth in vivo in autophagy-dependent but not in autophagy-independent breast tumors while combination treatment with autophagy inhibitors and other agent was preferentially synergistic in autophagy-dependent cells. These results imply that autophagy-dependence represents a tumor cell specific characteristic where autophagy inhibition will be more effective. Moreover, our results suggest that autophagy inhibition might be a potential therapeutic strategy for triple negative breast cancers, which currently lack an effective targeted treatment.

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Dual functions of autophagy in the response of breast tumor cells to radiation

Cited by 119 publications

References 48 publications

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D

STAT3-Mediated Autophagy Dependence Identifies Subtypes of Breast Cancer Where Autophagy Inhibition Can Be Efficacious

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