The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy

Gewirtz, David A.; Tyutyunyk‐Massey, Liliya; Landry, Joseph W.

doi:10.1016/j.bcp.2018.01.048

Cited by 8 publications

(8 citation statements)

References 48 publications

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“…It should be emphasized that these conclusions focus solely on the cell autonomous effects of autophagy inhibition. The potential utility of autophagy inhibition as a therapeutic strategy becomes even more complex when one further considers the cell non-autonomous impact of autophagy inhibition (81,91). Therefore, it is critical to emphasize, as previously stated (92), that an observation of a chemotherapeutic drug or radiation promoting autophagy in a tumor cell does not, of itself, predict the capacity of the autophagy to play a cytoprotective function and/or promote resistance; consequently, inhibition of the induced autophagy does not obligatorily represent a useful therapeutic approach for chemosensitization or radiosensitization.…”

Section: Discussionmentioning

confidence: 99%

Differential Radiation Sensitivity in p53 Wild-Type and p53-Deficient Tumor Cells Associated with Senescence but not Apoptosis or (Nonprotective) Autophagy

Patel

Saleh

et al. 2018

Radiation Research

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Studies of radiation interaction with tumor cells often focus on apoptosis as an end point; however, clinically relevant doses of radiation also promote autophagy and senescence. Moreover, functional p53 has frequently been implicated in contributing to radiation sensitivity through the facilitation of apoptosis. To address the involvement of apoptosis, autophagy, senescence and p53 status in the response to radiation, the current studies utilized isogenic H460 non-small cell lung cancer cells that were either p53-wild type (H460wt) or null (H460crp53). As anticipated, radiosensitivity was higher in the H460wt cells than in the H460crp53 cell line; however, this differential radiation sensitivity did not appear to be a consequence of apoptosis. Furthermore, radiosensitivity did not appear to be reduced in association with the promotion of autophagy, as autophagy was markedly higher in the H460wt cells. Despite radiosensitization by chloroquine in the H460wt cells, the radiation-induced autophagy proved to be essentially nonprotective, as inhibition of autophagy via 3-methyl adenine (3-MA), bafilomycin A1 or ATG5 silencing failed to alter radiation sensitivity or promote apoptosis in either the H460wt or H460crp53 cells. Radiosensitivity appeared to be most closely associated with senescence, which occurred earlier and to a greater extent in the H460wt cells. This finding is consistent with the in-depth proteomics analysis on the secretomes from the H460wt and H460crp53 cells (with or without radiation exposure) that showed no significant association with radioresistance-related proteins, whereas several senescence-associated secretory phenotype (SASP) factors were upregulated in H460wt cells relative to H460crp53 cells. Taken together, these findings indicate that senescence, rather than apoptosis, plays a central role in determination of radiosensitivity; furthermore, autophagy is likely to have minimal influence on radiosensitivity under conditions where autophagy takes the nonprotective form.

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Section: Discussionmentioning

confidence: 99%

Differential Radiation Sensitivity in p53 Wild-Type and p53-Deficient Tumor Cells Associated with Senescence but not Apoptosis or (Nonprotective) Autophagy

Patel

Saleh

et al. 2018

Radiation Research

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“…Most chemotherapeutic drugs as well as ionizing radiation promote autophagy in tumor cells (32)(33)(34)(35). However, autophagy can have both cell autonomous and cell nonautonomous effects and influence the outcome of therapy (35). Therefore, we evaluated whether the effects of NO are tumor cell autonomous or nonautonomous.…”

Section: Significancementioning

confidence: 99%

“…Cytokine Signature Showed That NO Suppresses TAMs Affecting CRPC TME. The cell nonautonomous effects are related largely to the immune system (35), TME, and subclone heterogeneity (36). Macrophages are known to increase specific circulating cytokines with progressive metastasis (37,38).…”

Section: Significancementioning

confidence: 99%

Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth

Arora

Panara

Kuchakulla

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Immune targeted therapy of nitric oxide (NO) synthases are being considered as a potential frontline therapeutic to treat patients diagnosed with locally advanced and metastatic prostate cancer. However, the role of NO in castration-resistant prostate cancer (CRPC) is controversial because NO can increase in nitrosative stress while simultaneously possessing antiinflammatory properties. Accordingly, we tested the hypothesis that increased NO will lead to tumor suppression of CRPC through tumor microenvironment. S-nitrosoglutathione (GSNO), an NO donor, decreased the tumor burden in murine model of CRPC by targeting tumors in a cell nonautonomous manner. GSNO inhibited both the abundance of antiinflammatory (M2) macrophages and expression of pERK, indicating that tumor-associated macrophages activity is influenced by NO. Additionally, GSNO decreased IL-34, indicating suppression of tumor-associated macrophage differentiation. Cytokine profiling of CRPC tumor grafts exposed to GSNO revealed a significant decrease in expression of G-CSF and M-CSF compared with grafts not exposed to GSNO. We verified the durability of NO on CRPC tumor suppression by using secondary xenograft murine models. This study validates the significance of NO on inhibition of CRPC tumors through tumor microenvironment (TME). These findings may facilitate the development of previously unidentified NO-based therapy for CRPC.

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“…However, over-expression of autophagy inducing microRNAs (miR-NAs) such as mir-15a and mir-16 have yielded promising sensitization effect [92]. When considering autophagy inhibition in therapy, an important contributing factor is its critical role in immune system function, and that global autophagy inhibition may result in immune-suppression, resulting in a pro-tumourigenic environment [93]. Furthermore, cancer ADCD has been observed in response to both global and targeted autophagy induction in the absence of chemotherapy [94][95][96].…”

Section: Autosis Induction As Treatment Modalitymentioning

confidence: 99%

The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

Kriel

Loos

2019

Cell Death Differ

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The recent discovery of autosis as a variant of autophagy-dependent cell death has challenged the conventional understanding of cell death and programmed cell death in cellular decision making. In contrast to previous accounts of distinct cell death modalities, autosis occurs with high autophagic activity, in the absence of apoptotic and necrotic markers and yet is not fully regulated by typical autophagy markers. Given the metabolic importance of autophagic responses and the extensive cross-talk with both apoptosis and necrosis signalling, the classical and morphotype-driven characterization of cell death as pre-determined subroutines is being increasingly called into question. Furthermore, the conflicting evidence with regards to cell death induction through autophagy modulation in various cancer models highlights the lack of consensus over the extent to which autophagy assists in cell death ontrol and whether it is capable of being a bona fide lethal process. This review evaluates the evidence and context of autophagy-dependent cell death and delineates the role of an autophagic flux threshold associated with 'lethal' and 'non-lethal' autophagy and its role in autosis control. In doing so, cancer treatment avenues will be explored with regards to precision modulation of tumour autophagic flux to ascertain whether autosis induction may present a novel therapeutic strategy.

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The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy

Cited by 8 publications

References 48 publications

Differential Radiation Sensitivity in p53 Wild-Type and p53-Deficient Tumor Cells Associated with Senescence but not Apoptosis or (Nonprotective) Autophagy

Differential Radiation Sensitivity in p53 Wild-Type and p53-Deficient Tumor Cells Associated with Senescence but not Apoptosis or (Nonprotective) Autophagy

Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth

The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

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