Autophagy in endocrine tumors

Weckman, Andrea; Rotondo, Fabio; Ieva, Antonio Di; Syro, Luis V.; Butz, Henriett; Cusimano, Michael D.; Kovács, Kálmán

doi:10.1530/erc-15-0042

Cited by 31 publications

(14 citation statements)

References 78 publications

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“…14 That is the reason why we investigated the effect of miR-18a on autophagy. As shown in Figure 5a, overexpression of miR-18a-5p significantly induced GFP/mRFP-LC3 dot accumulation.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

et al. 2017

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Lung cancer is the major form of cancer resulting in cancer-related mortality around the world. MicroRNAs are endogenous small non-coding single-stranded RNAs, which can engage in the regulation of gene expression. In this study, miR-18a-5p significantly upregulated in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines, suggesting an oncogenic function in lung cancer. Additionally, miR-18a-5p can promote carcinogenesis by directly targeting interferon regulatory factor 2 (IRF2). Further experiments indicated that IRF2 can increase cell apoptosis, inhibit cell proliferation and migration ability. Our study demonstrates that miR-18a-5p promotes autophagy in NSCLC. Collectively, these results indicate that miR-18a-5p can not only promote NSCLC by suppressing IRF2, but also will be a promising target in the near future.

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“…14 That is the reason why we investigated the effect of miR-18a on autophagy. As shown in Figure 5a, overexpression of miR-18a-5p significantly induced GFP/mRFP-LC3 dot accumulation.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

et al. 2017

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“…Although it is not clear whether there is a crosstalk between PI3K/AKT/mTOR/p70S6K and MAPK/ERK pathway to regulate autophagy, it has been suggested that RAS protein might be involved in the intersection of MAPK/ERK and PI3K/AKT signaling pathways. RAS stimulates autophagy when the MAPK signaling pathway is activated, while inhibits autophagy when PI3K/AKT is activated (Furuta et al 2004, Morani et al 2014, Netea-Maier et al 2015, Weckman et al 2015. Whether an alternative pathway, involved in the TSHinduced activation of p70S6K in normal cells, may play a role in autophagy induction in thyroid cells, need further investigation.…”

Section: Discussionmentioning

confidence: 99%

FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner

Nozima

Mendes

Pereira

et al. 2019

Endocrine-Related Cancer

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We previously proposed that high expression of FAM129A can be used as a thyroid carcinoma biomarker in preoperative diagnostic exams of thyroid nodules. Here, we identify that FAM129A expression is increased under nutrient and growth factor depletion in a normal thyroid cell line (PCCL3), overlapping with increased expression of autophagyrelated protein and inhibition of AKT/mTOR/p70S6K. Supplementation of insulin, TSH and serum to the medium was able to reduce the expression of both FAM129A and autophagyrelated protein and reestablish the AKT/mTOR/p70S6K axis. To determine the direct role of FAM129A on autophagy, FAM129A was transfected into PCCL3 cells. Its overexpression induced autophagic vesicles formation, evidenced by transmission electron microscopy. Co-expression of FAM129A and mCherry-EGFP-LC3B in PCCL3 showed an increased yellow puncta formation, suggesting that FAM129Ainduces autophagy. To further confirm its role on autophagy, we knockdown FAM129A in two thyroid carcinoma cell lines (TPC1 and FTC-236). Unexpectedly, FAM129A silencing increased autophagic flux, suggesting that FAM129A inhibits autophagy in these models. We next co-transfected PCCL3 cells with FAM129A and RET/PTC1 and tested autophagy in this context. Co-expression of FAM129A and RET/PTC1 oncogene in PCCL3 cells, inhibited RET/PTC1-induced autophagy. Together, our data suggest that, in normal cells FAM129A induces autophagy in order to maintain cell homeostasis and provide substrates under starvation conditions. Instead, in cancer cells, decreased autophagy may help the cells to overcome cell death. FAM129A regulates autophagy in a cell-and/or context-dependent manner. Our data reinforce the concept that autophagy can be used as a strategy for cancer treatment.

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“…Interestingly, it appears that autophagy is in a mutual relation with the process of apoptosis, and that this interconnection is context-dependent; it has been shown that autophagy may facilitate apoptosis or necrosis (Marino et al 2014). Therefore, autophagy has been exploited as a possible therapeutic strategy (O'Reilly et al 2006, Amaravadi et al 2016 in different tumor models, including glioma, glioblastoma, neuroblastoma and breast cancer, and in some NEN models (Amaravadi et al 2007, Degtyarev et al 2008, Fan et al 2010, Xu et al 2011, Hong et al 2013, Seitz et al 2013, Weckman et al 2015. Chloroquine (CQ), commonly used in the treatment of malaria and of rheumatic autoimmune disorders, inhibits lysosomal hydrolase activity and consequently autophagy.…”

Section: :6mentioning

confidence: 99%

Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model

Avniel-Polak

Leibowitz

Doviner

et al. 2018

Endocrine-Related Cancer

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Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.

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Autophagy in endocrine tumors

Cited by 31 publications

References 78 publications

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner

Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model

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