Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells

Huang, Yao Huei; Yang, Pei Ming; Chuah, Qiu Yu; Lee, Yi Jang; Hsieh, Yi Fen; Peng, Chih Wen; Chiu, Shu Jun

doi:10.4161/auto.28772

Cited by 64 publications

(51 citation statements)

References 47 publications

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“…57 Breast cancer cells exposed to radiation-induced DNA damage trigger autophagy and senescence, and suppression of autophagy increases apoptosis in an amount that is similar to the reduction in senescence. Similar to our results, the combination of radiationC3MA is more cytotoxic than the combination of radiationCBafA1, 58 supporting the proapoptotic effect of early autophagy inhibition with 3MA.…”

Section: Discussionsupporting

confidence: 91%

Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

et al. 2015

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Abbreviations: 3MA, 3-methyladenine; AO, acridine orange; BafA1, bafilomycin A 1 ; CDKN1A/p21, cyclin-dependent kinase inhibitor 1A (p21, Cip1); cP1-4, cellular population 1 to 4; CPD, cumulative population doubling; DDR, DNA damage response; DFM, drug-free medium; H2AFX, H2A histone family, member X; MAP1LC3A/LC3, microtubule-associated protein 1 light chain 3 a; MTOR, mechanistic target of rapamycin; MTORC1, MTOR complex 1; NA, nuclear area; NMA, nuclear morphometric analysis; nP1-5, nuclear population 1 to 5; PRKAA/AMPKa, protein kinase, AMP-activated; RAPA, rapamycin; RPTOR/RAPTOR, regulatory-associated protein of MTOR, complex 1; SA-b-gal, senescence associated b-galactosidase assay; SQSTM1/p62, sequestosome 1; TMZ, temozolomide.Autophagy and senescence have been described as central features of cell biology, but the interplay between these mechanisms remains obscure. Using a therapeutically relevant model of DNA damage-induced senescence in human glioma cells, we demonstrated that acute treatment with temozolomide induces DNA damage, a transitory activation of PRKAA/AMPK-ULK1 and MAPK14/p38 and the sustained inhibition of AKT-MTOR. This produced a transient induction of autophagy, which was followed by senescence. However, at the single cell level, this coordinated transition was not observed, and autophagy and senescence were triggered in a very heterogeneous manner. Indeed, at a population level, autophagy was highly negatively correlated with senescence markers, while in single cells this correlation did not exist. The inhibition of autophagy triggered apoptosis and decreased senescence, while its activation increased temozolomide-induced senescence, showing that DNA damage-induced autophagy acts by suppressing apoptosis.

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Section: Discussionsupporting

confidence: 91%

Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

et al. 2015

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“…Radiotherapy is one of the best therapeutic choices for cancer treatment (26). Radiation-induced autophagy in cancer cell lines is related to cell death mechanism and autophagyinducing agents may act especially as radio-sensitizers or radio-resistance (128).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, autophagy is important to the radiation-induced senescence. Inhibition of autophagy results in a switch from radiation-induced senescence to apoptosis in breast cancer cells (26).…”

Section: The Role Of Autophagy In Radiotherapymentioning

confidence: 99%

Crosstalk between autophagy and intracellular radiation response (Review)

Wang

Huang

et al. 2016

International Journal of Oncology

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Abstract. Autophagy induced by radiation is critical to cell fate decision. Evidence now sheds light on the importance of autophagy induced by cancer radiotherapy. Traditional view considers radiation can directly or indirectly damage DNA which can activate DNA damage the repair signaling pathway, a large number of proteins participating in DNA damage repair signaling pathway such as p53, ATM, PARP1, FOXO3a, mTOR and SIRT1 involved in autophagy regulation. However, emerging recent evidence suggests radiation can also cause injury to extranuclear targets such as plasma membrane, mitochondria and endoplasmic reticulum (ER) and induce accumulation of ceramide, ROS, and Ca 2+ concentration which activate many signaling pathways to modulate autophagy. Herein we review the role of autophagy in radiation therapy and the potent intracellular autophagic triggers induced by radiation. We aim to provide a more theoretical basis of radiation-induced autophagy, and provide novel targets for developing cytotoxic drugs to increase radiosensitivity. Contents1. Introduction 2. The role of autophagy in radiotherapy 3. DNA damage repair and autophagy 4. Mitochondrial damage and autophagy 5. ER stress and autophagy 6. ROS and autophagy 7. Ceramide and autophagy 8. Ca 2+ and autophagy 9. Targeting autophagy for radiotherapy 10. Conclusion IntroductionRadiotherapy is an effective strategy for the treatment of many kinds of cancer to kill or control the malignant tumor cells. However, its benefits have been limited due to radiation resistance. It is imperative to identify new targets and develop cytotoxic drugs to increase radiosensitivity. Radiosensitization has traditionally been performed with agents known to induce apoptosis. However, recent studies demonstrate autophagy induced by radiation also plays an important role in cancer Crosstalk between autophagy and intracellular radiation response (Review)

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“…In addition to apoptosis of cancer cells, radiation can result in senescence of cancer cells, a phenomenon of prolonged cell cycle arrest [50]. These senescent cells are metabolically active; therefore, they ultimately develop senescence-associated secretory phenotypes and secrete cytokines, chemokines, growth factors, and proteases, as well as insoluble extracellular matrix components that promote tumor progression via invasion and migration of neighboring non-irradiated cancer cells through JAK2-STAT3 pathway activation [50,51].…”

Section: Increase In Radiosensitivity With Pharmacologic Autophagy Inmentioning

confidence: 99%

Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

Liang

El‐Zein²,

Dave

2015

J Nucl Med Radiat Ther

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Currently, many breast cancer patients with localized breast cancer undergo breast-conserving therapy, consisting of local excision followed by radiation therapy. Following radiation therapy, breast cancer cells are noted to undergo induction of autophagy, development of radioresistance, and enrichment of breast cancer stem cell subpopulations. It is hypothesized that inhibition of the cytoprotective autophagy that arises following radiation therapy increases radiosensitivity and confers longer relapse-free survival by eliminating tumor-initiating breast cancer stem cells. Therefore, we reviewed the controversial role of autophagy in breast cancer tumorigenesis and progression, autophagy induction by radiotherapy, and utilization of autophagy inhibitors to increase radiosensitivity of breast cancer and to target radioresistant breast cancer stem cells.

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Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells

Cited by 64 publications

References 47 publications

Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

Crosstalk between autophagy and intracellular radiation response (Review)

Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

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