Tauroursodeoxycholic acid mediates endoplasmic reticulum stress and autophagy in adrenocortical carcinoma cells

Huang, Xuemei; Wu, Lili; Kuang, Yaqi; Li, Xin; Deng, Xiujun; Liang, Xinghuan; Li, Li; Yang, Haiyan; Huang, Zhenxing; Lu, Di; Luo, Zuojie

doi:10.3892/ol.2019.11057

Cited by 6 publications

(6 citation statements)

References 37 publications

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“…The mechanism underlying the cytotoxic effect of Pg on TVBF-7 was seemingly linked to an increase in LC3-II levels, representing the activation of autophagy. The role of autophagy in the ACC context is challenging because it plays a double-edged role not only as a survival response to chemotherapeutic drugs, resulting in treatment failure, but also as an important mechanism underlying tumor cell suicide [ 35 , 36 , 37 ]. The cytoprotective function of autophagy is activated in many circumstances by suppressing apoptosis, and this evidence justifies the observation of an increase in the cell viability in TVBF-7 cells exposed to Pg.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

Tamburello

Abate

Rossini

et al. 2023

IJMS

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Background: Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. Methods: NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Results: Progesterone significantly reduced xenograft tumor area and metastasis formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastaticcells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Conclusion: Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

Tamburello

Abate

Rossini

et al. 2023

IJMS

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“…Importantly, proliferation, migration and invasion studies were performed at 24 hours following TUDCA treatment while analysis of ER stress, autophagy and apoptosis was carried out upon 48 hours of treatment. These different time-points may explain the dissimilar results obtained when compared with the previous report (37). The association between ER stress and autophagy was also reported in another adrenal tumor model, PCC (38).…”

Section: Pro-survival Role Of Autophagy In Adrenal Tumors and Its Imp...mentioning

confidence: 74%

Modulation of Autophagy in Adrenal Tumors

Sousa

Pereira²,

Pignatelli³

2022

Front. Endocrinol.

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Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast, the rare adrenal malignant tumors are often highly aggressive and with poor prognosis. Besides usually being detected in advanced stages, often already with metastases, one of the reasons of the unfavorable outcome of the patients with adrenal cancer is the absence of effective treatments. Autophagy is one of the intracellular pathways targeted by several classes of chemotherapeutics. Mitotane, the most commonly used drug for the treatment of adrenocortical carcinoma, was recently shown to also modulate autophagy. Autophagy is a continuous programmed cellular process which culminates with the degradation of cellular organelles and proteins. However, being a dynamic mechanism, understanding the autophagic flux can be highly complex. The role of autophagy in cancer has been described paradoxically: initially described as a tumor pro-survival mechanism, different studies have been showing that it may result in other outcomes, namely in tumor cell death. In adrenal tumors, this dual role of autophagy has also been addressed in recent years. Studies reported both induction and inhibition of autophagy as a treatment strategy of adrenal malignancies. Importantly, most of these studies were performed using cell lines. Consequently clinical studies are still required. In this review, we describe what is known about the role of autophagy modulation in treatment of adrenal tumors. We will also highlight the aspects that need further evaluation to understand the paradoxical role of autophagy in adrenal tumors.

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“…The mechanism underlying the cytotoxic effect of Pg on TVBF-7, seemed to be linked to an increase in LC3-II levels, representing the activation of autophagy. The role of autophagy in the ACC context is challenging because it plays a double-edged role as a survival response to chemotherapeutic drugs, resulting in treatment failure, but also as an important mechanism underlying tumor cell suicide (Huang et al, 2019;Sousa et al, 2022;Tompkins et al, 2019). The cytoprotective function of autophagy is activated in many circumstances by suppressing apoptosis and this evidence justifies the observation of an increase in the cell viability in TVBF-7 cells exposed to Pg.…”

Section: Discussionmentioning

confidence: 89%

Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines

Tamburello

Abate

Rossini

et al. 2022

Preprint

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Background and Purpose: Adrenocortical cancer (ACC) is a rare malignant neoplasm with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug useful in ACC, in line with other studies that demonstrated its antitumoral effect in other cancers. Experimental Approach: NCI-H295R, MUC-1, and TVBF-7 ACC cell lines were used. Cell apoptosis and cell cycle were analyzed by flow cytometry. Cell migration and invasiveness were studied using transwell assays, and metalloprotease 2 activity by zymography. Cell xenografts in zebrafish embryos were performed by measuring both the tumor areas and the number of embryos with metastasis. Key Results: Progesterone exerted a long-lasting cytotoxic effect in metastatic cell lines, MUC-1 and TVBF-7. Progesterone caused apoptosis in NCI-H295R and MUC-1 cells, inducing changes in the cell cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. In the zebrafish embryos, progesterone significantly reduced each ACC cell line’s xenograft tumor area and metastasis formation in embryos injected with metastatic cells. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Conclusion and Implications: Our results give support to the role of progesterone in ACC. The involvement of its analogous (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.

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Tauroursodeoxycholic acid mediates endoplasmic reticulum stress and autophagy in adrenocortical carcinoma cells

Cited by 6 publications

References 37 publications

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

Modulation of Autophagy in Adrenal Tumors

Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines

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