The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation

Patel, Nipa; Sohal, Sahib S.; Manjili, Masoud H.; Harrell, J. Chuck; Gewirtz, David A.

doi:10.1667/rade-20-00009

Cited by 53 publications

(23 citation statements)

References 137 publications

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“…Still, senescence can be induced without p53 [ 42 , 79 ]. In the absence of strong senescence markers ( Figure 2 ), we suspect that STS117 undergo mitotic catastrophe, which is the main cellular response to RT-induced DNA damage, especially in the absence of functional check points such as p53 [ 16 , 19 , 80 ] and can drive cells toward cell death by either apoptosis or necrosis or toward senescence. Given the low level of cell death in STS117 after RT ( Figure 1 and Figure 4 ), mitotic slippage in STS117 likely resulted in senescence.…”

Section: Discussionmentioning

confidence: 99%

“…Cell fates include autophagy, cell cycle arrest, senescence, mitotic catastrophe, necrosis and apoptosis [ 14 , 15 , 16 ]. In particular, therapy-induced senescence (TIS) is a well-described response in many cancer types [ 15 , 17 , 18 ] that is triggered by a variety of stresses, such as RT-induced DNA damage [ 19 ]. Senescent cells are characterized by several hallmarks associated with their biological function such as proliferation arrest [ 20 , 21 ], senescence associated beta-galactosidase (SA-β-gal) activity [ 22 , 23 ], persistent DNA damage [ 24 , 25 ] and active senescence associated secretory phenotype (SASP) [ 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells

Lafontaine

Cardin

Malaquin

et al. 2021

Cancers

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Radiotherapy (RT) is a key component of cancer treatment. Most of the time, radiation is given after surgery but for soft-tissue sarcomas (STS), pre-surgical radiation is commonly utilized. However, despite improvements in RT accuracy, the rate of local recurrence remains high and is the major cause of death for patients with STS. A better understanding of cell fates in response to RT could provide new therapeutic options to enhance tumour cell killing by RT and facilitate surgical resection. Here, we showed that irradiated STS cell cultures do not die but instead undergo therapy-induced senescence (TIS), which is characterized by proliferation arrest, senescence-associated β-galactosidase activity, secretion of inflammatory cytokines and persistent DNA damage. STS-TIS was also associated with increased levels of the anti-apoptotic Bcl-2 family of proteins which rendered cells targetable using senolytic Bcl-2 inhibitors. As oppose to radiation alone, the addition of senolytic agents Venetoclax (ABT-199) or Navitoclax (ABT-263) after irradiation induced a rapid apoptotic cell death in STS monolayer cultures and in a more complex three-dimensional culture model. Together, these data suggest a new promising therapeutic approach for sarcoma patients who receive neoadjuvant RT. The addition of senolytic agents to radiation treatments may significantly reduce tumour volume prior to surgery and thereby improve the clinical outcome of patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells

Lafontaine

Cardin

Malaquin

et al. 2021

Cancers

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“…On the other hand, some recent data indicated that radioresistance appeared to be most closely associated with senescence occurring earlier and more significant in the p53wt NSCLC cells [ 99 ]. In the light of a tumor dormancy model, a phase of proliferative recovery in a subset of cells frequently following after the radiation-induced senescence can contribute to therapy resistance and conceivably the disease relapse [ 100 , 101 ]. In this regard, such an impact of senescence will open up a new avenue for novel senolytics that await clinical prove as an adjuvant to radiotherapy to prolong remission by delaying disease recurrence in patients.…”

Section: Discussionmentioning

confidence: 99%

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

Pustovalova

Alhaddad

Blokhina

et al. 2021

IJMS

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Ionizing radiation (IR) is used for patients diagnosed with unresectable non-small cell lung cancer (NSCLC). However, radiotherapy remains largely palliative due to the survival of specific cell subpopulations. In the present study, the sublines of NSCLC cells, A549IR (p53wt) and H1299IR (p53null) survived multifraction X-ray radiation exposure (MFR) at a total dose of 60 Gy were investigated three weeks after the MFR course. We compared radiosensitivity (colony formation), expression of epithelial-mesenchymal transition (EMT) markers, migration activity, autophagy, and HR-dependent DNA double-strand break (DSB) repair in the bulk and entire CD44high/CD166high CSC-like populations of both parental and MFR survived NSCLC cells. We demonstrated that the p53 status affected: the pattern of expression of N-cadherin, E-cadherin, Vimentin, witnessing the appearance of EMT-like phenotype of MFR-surviving sublines; 1D confined migratory behavior (wound healing); the capability of an irradiated cell to continue to divide and form a colony of NSCLC cells before and after MFR; influencing the CD44/CD166 expression level in MFR-surviving NSCLC cells after additional single irradiation. Our data further emphasize the impact of p53 status on the decay of γH2AX foci and the associated efficacy of the DSB repair in NSCLC cells survived after MFR. We revealed that Rad51 protein might play a principal role in MFR-surviving of p53 null NSCLC cells promoting DNA DSB repair by homologous recombination (HR) pathway. The proportion of Rad51 + cells elevated in CD44high/CD166high population in MFR-surviving p53wt and p53null sublines and their parental cells. The p53wt ensures DNA-PK-mediated DSB repair for both parental and MFR-surviving cells irrespectively of a subsequent additional single irradiation. Whereas in the absence of p53, a dose-dependent increase of DNA-PK-mediated non-homologous end joining (NHEJ) occurred as an early post-irradiation response is more intensive in the CSC-like population MFR-surviving H1299IR, compared to their parental H1299 cells. Our study strictly observed a significantly higher content of LC3 + cells in the CD44high/CD166high populations of p53wt MFR-surviving cells, which enriched the CSC-like cells in contrast to their p53null counterparts. The additional 2 Gy and 5 Gy X-ray exposure leads to the dose-dependent increase in the proportion of LC3 + cells in CD44high/CD166high population of both parental p53wt and p53null, but not MFR-surviving NSCLC sublines. Our data indicated that autophagy is not necessarily associated with CSC-like cells’ radiosensitivity, emphasizing that careful assessment of other milestone processes (such as senescence and autophagy-p53-Zeb1 axis) of primary radiation responses may provide new potential targets modulated for therapeutic benefit through radiosensitizing cancer cells while rescuing normal tissue. Our findings also shed light on the intricate crosstalk between autophagy and the p53-related EMT, by which MFR-surviving cells might obtain an invasive phenotype and metastatic potential.

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“…Over the last years, senescence has been considered an important process to fight cancer, encouraging the search for anti-cancer therapies based on the induction of cell senescence (92)(93)(94). However, studies based on therapy-induced senescence (TIS) indicated the emergence of adverse effects on cancer treatment (95,96). Chemotherapy-induced SASP drives bone loss in breast cancer and its regulation by p38-MAPK-MK2 inhibition could preserve bone, improving the quality of life of patients (97).…”

Section: The Dual Interface Of Autophagy and Senescencementioning

confidence: 99%

Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy

et al. 2020

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The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of senescence-associated secretory proteins by autophagy lead to a senescent phenotype. Besides disturbing tumor treatment responses, autophagy also participates in innate and adaptive immune signaling. Furthermore, recent studies have indicated intricate crosstalk between autophagy and the epithelial-mesenchymal transition (EMT), by which cancer cells obtain an invasive phenotype and metastatic potential. Thus, autophagy in the cancer context is far broader and complex than just a cell energy sensing mechanism. In this scenario, we will discuss the key roles of autophagy in the TME and surrounding cells, contributing to cancer development and progression/EMT. Finally, the potential intervention in autophagy processes as a strategy for cancer therapy will be addressed.

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The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation

Abstract: BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access titles in the biological, ecological, and environmental sciences published by nonprofit societies, associations, museums, institutions, and presses.

Cited by 53 publications

References 137 publications

Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells

Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy

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