Hypoxia-Induced Autophagy Confers Resistance of Breast Cancer Cells to Ionizing Radiation

He, Wenshan; Dai, Xin; Jin, Min; Liu, Cuiwei; Rent, Jing-Hua

doi:10.3727/096504013x13589503483012

Cited by 58 publications

(37 citation statements)

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“…Hypoxia reflects dynamic microenvironmental conditions in solid tumours, limits responses to radiotherapy [93] and some chemotherapeutic and anti-endocrine agents [94,95], drives genomic instability and is generally associated with progression to invasive/metastatic disease [96,97]. Tumour-stromal interactions change under hypoxic conditions to promote tumour progression via the activity of enzymes such as LOX [98], angiogenic factors and infiltrating macrophages [99,100].…”

Section: Resultsmentioning

confidence: 99%

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

et al. 2013

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IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

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Section: Resultsmentioning

confidence: 99%

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

et al. 2013

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“…Other autophagy-related proteins, such as Atg3 and Atg4 mediate protein-phospholipid complexes that are localized to autophagosomal membranes [44]. Hypoxia-induced autophagy leads to a marked accumulation of autophagosomes along with RNA induction of autophagy-related genes such as Beclin-1, Atg5, and Atg12, and ultimately, to radioresistance [45]. On the other hand, inhibition of autophagy-related genes with small interfering RNA results in retardation of DNA double-strand breaks repair, and thus, leads to radiosensitization [45].…”

Section: Autophagy and Radiotherapymentioning

confidence: 99%

Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

Liang

El‐Zein²,

Dave

2015

J Nucl Med Radiat Ther

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Currently, many breast cancer patients with localized breast cancer undergo breast-conserving therapy, consisting of local excision followed by radiation therapy. Following radiation therapy, breast cancer cells are noted to undergo induction of autophagy, development of radioresistance, and enrichment of breast cancer stem cell subpopulations. It is hypothesized that inhibition of the cytoprotective autophagy that arises following radiation therapy increases radiosensitivity and confers longer relapse-free survival by eliminating tumor-initiating breast cancer stem cells. Therefore, we reviewed the controversial role of autophagy in breast cancer tumorigenesis and progression, autophagy induction by radiotherapy, and utilization of autophagy inhibitors to increase radiosensitivity of breast cancer and to target radioresistant breast cancer stem cells.

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“…In the tumour microenvironment, limited availability of oxygen and nutrients, such as glucose and amino acids, and an accumulation of lactic acid result in the hypoxic and acidic conditions that allow tumour cells to metastasize . Hypoxia promotes the accumulation of autophagosomes by inducing the expression of autophagy‐related genes, such as Beclin‐1, ATG5, ATG7 and ATG12 . Cancer cells survive the stressful conditions of the tumour microenvironment by adapting to hypoxia through intracellular degradation and autophagy .…”

Section: Introductionmentioning

confidence: 99%

PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

Weng

Jia

et al. 2020

J Cellular Molecular Medi

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Pancreatic ductal adenocarcinoma (PDAC) tumours exhibit a high level of heterogeneity which is associated with hypoxia and strong resistance to chemotherapy. The RNA splicing protein polypyrimidine tract‐binding protein 3 (PTBP3) regulates hypoxic gene expression by selectively binding to hypoxia‐regulated transcripts. We have investigated the role of PTBP3 in tumour development and chemotherapeutic resistance in human PDAC tissues and pancreatic cancer cells. In addition, we determined the sensitivity of cancer cells to gemcitabine with differential levels of PTBP3 and whether autophagy and hypoxia affect gemcitabine resistance in vitro. PTBP3 expression was higher in human pancreatic cancer than in paired adjacent tissues. PTBP3 overexpression promoted PDAC proliferation in vitro and tumour growth in vivo, whereas PTBP3 depletion had opposing effects. Hypoxia significantly increased the expression of PTBP3 in pancreatic cancer cells in vitro. Under hypoxic conditions, cells were more resistance to gemcitabine. Knockdown of PTBP3 results in decreased resistance to gemcitabine, which was attributed to attenuated autophagy. We propose that PTBP3 binds to multiple sites in the 3′‐UTR of ATG12 resulting in overexpression. PTBP3 increases cancer cell proliferation and autophagic flux in response to hypoxic stress, which contributes to gemcitabine resistance.

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Hypoxia-Induced Autophagy Confers Resistance of Breast Cancer Cells to Ionizing Radiation

Cited by 58 publications

References 0 publications

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

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