Autophagy as a modulator and target in prostate cancer

Farrow, Jason; Yang, Joy C.; Evans, Christopher P.

doi:10.1038/nrurol.2014.196

Cited by 139 publications

(143 citation statements)

References 75 publications

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“…9,68 In clinical trials, EGFR-TKIs have been used to treat patients with lung cancer 9 and prostate cancer. 57 Although the combination of an anticancer agent with an autophagy inhibitor is designed to synergize cell death of cancer cells, 56,60,61 based on our findings, the same strategy might not be suitable for the combination of an EGFR-TKI and an autophagy inhibitor such as 3-MA or spautin-1. We found gefitinib or erlotinib increased autophagic flux promoting cell death.…”

Section: Discussionmentioning

confidence: 95%

“…[56][57][58][59][60][61][62] The downstream inhibitors of autophagy chloroquine and hydroxychloroquine suppress tumor growth in a laboratory mouse model 63 and have been used in clinical trials of human patients. 56,[59][60][61][62]64 In a clinical trial, the addition of chloroquine has significantly improved median survival of patients with glioblastoma receiving conventional chemotherapy and radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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(2016) Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia, Autophagy, 12:6, 1029-1046, DOI: 10.1080/15548627.2016 ABSTRACTAutophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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“…Although Zannah group suggested that HCQ in combination with the antidiabetic, biguanide drug metformin reduces blood glucose and lipid profile levels significantly in rats, clinically there are no interactions between HCQ and metformin [24,25]. Another interesting story based on their autophagy inhibiting property, recent several clinical studies suggest that CQ enhances the metformin-induced cell apoptosis and intensify the metformin-induced inhibition of cell proliferation of breast-and other cancers [26][27][28]. Reduced glucose levels or hypoglycaemia have also been reported with mefloquine and quinine [8,29].…”

Section: Antidiabeticsmentioning

confidence: 99%

Clinically Significant Drug Interaction Profiles of Chloroquine Analogues with Adverse Consequences and Risk Management

Al‐Bari¹,

Islam²

2015

J. Sci. Res.

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The popularity of chloroquine (CQ) analogues, for malaria treatment in many countries emanates from it being cheap, widely available, relatively well tolerated, and having a rapid onset of action. Thus, CQ analogues are commonly sold as over-the-counter (OTC) medications. CQ analogues like hydroxychloroquine (HCQ) alone and/or other drugs in combination have been used as anti-inflammatory and immunomodulatory drugs in the treatment of various rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, dermatomyositis, Sjögren's syndrome, chronic juvenile arthritis, psoriatic arthritis, and have shown clinical benefits with an acceptable safety profile. As anti-inflammatory mechanism, CQ inhibits pro-inflammatory cytokine release, antigen processing and blocking the actions of histamine and phospholipase A 2 . CQ analogue has also been studied for its potential as an enhancing agent in cancer therapies in various clinical trials. In many cases, the lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity to inhibit inflammatory disorders. Moreover, it is indicated that the efficacy of conventional therapies can be dramatically enhanced if CQ analogues are given in combination. Although majority of CQ analogue in combination therapies improves overall the outcome, such treatments are often associated with serious toxicities leading to fatal.

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“…A number of studies have suggested that CQ can inhibit autophagy through the prevention of lysosome acidification, and subsequently, the inhibition of autophagosome-lysosome fusion, to block the degradation of autolysosomes at the last step of autophagy (8,9). Previous studies have indicated that CQ exhibited an antitumor effect on several types of cancer, including glioblastoma (10,11), hepatocellular carcinoma (12), breast cancer (13), prostate cancer (14) and pancreatic cancer (15), which prompts us to hypothesize that CQ may be able to influence the growth of esophageal carcinoma through the modulation of autophagy. Therefore, the aim of the present study is to explore the antitumor effect of CQ on the esophageal squamous carcinoma cell line EC109, and the potential mechanism for this effect.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells inï¿½vitro

Cai

et al. 2017

Oncol Lett

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Abstract. Esophageal carcinoma is a malignancy that severely threatens human health, with a high incidence rate and a low 5-year survival rate. Resistance to chemotherapy frequently emerges during its treatment, partly due to the induction of autophagy. Therefore, targeting autophagy may be a promising therapeutic approach for the treatment of esophageal carcinoma. In the present study, it was investigated how chloroquine (CQ) can influence the growth ability and biological behaviors of EC109 esophageal squamous carcinoma cells in vitro, as well as the potential molecular mechanisms behind its activity. It was demonstrated that CQ could suppress the growth and proliferation of EC109 cells in a time-and dose-dependent manner; migration and colony formation abilities were also inhibited by CQ. Furthermore, subsequent to the exposure to CQ, the number of autophagosomes was clearly increased in EC109 cells overexpressing green fluorescent protein tagged-light chain (LC)3 when observed by fluorescence microscopy. Protein expression of the endogenous autophagy markers LC3-II and p62 was elevated subsequent to CQ treatment, whereas the expression of proteins from the protein kinase B/mechanistic target of rapamycin target of rapamycin pathway was inhibited. This suggested that CQ could induce the formation of autophagosomes in the initiation of autophagy, but inhibit the degradation of autophagosomes in a later stage of autophagy. The overall effect was that autophagic cell death was activated by CQ, as confirmed by flow cytometry. Overall, the anticancer effect of chloroquine on EC109 was revealed to be mediated through modulating autophagy, and this may produce promising therapeutic benefits for esophageal carcinoma.

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Autophagy as a modulator and target in prostate cancer

Cited by 139 publications

References 75 publications

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Clinically Significant Drug Interaction Profiles of Chloroquine Analogues with Adverse Consequences and Risk Management

Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells inï¿½vitro

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