Therapeutic Targeting of Autophagy for Renal Cell Carcinoma Therapy

Jones, Trace M.; Carew, Jennifer S.; Nawrocki, Steffan T.

doi:10.3390/cancers12051185

Cited by 37 publications

(36 citation statements)

References 90 publications

(78 reference statements)

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“…It has been reported that about 33% of RCC has already metastasized at the first diagnosis, and 20% ~ 50% of patients will progress to metastasis following surgery [6,1]. Despite ccRCC treatment has developed for decades, the advanced and metastatic ccRCCs are still challenging due to its resistance to chemo-and radiotherapy, therefore RCC patients are still confronted with worse prognosis [1]. Although enormous efforts about identifying appropriate biomarkers for ccRCC tumorigenesis, progression and aggressiveness have been made to improve the efficiency of ccRCC diagnosis and prognosis, to date fewer particular biomarkers exhibit satisfactory potential for ccRCC classification and prognosis prediction or is ready for widespread use in clinical application [1,20].…”

Section: Discussionmentioning

confidence: 99%

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G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

Yang¹,

Zhang²,

Ni³

et al. 2020

Preprint

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Background: Clear cell renal cell carcinoma (ccRCC) is a cell metabolic disease with high metastasis rate and poor prognosis. Our previous studies demonstrate that glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is highly expressed in ccRCC and predicts poor outcomes of ccRCC patients. The aims of this study were to confirm the oncogenic role of G6PD in ccRCC and unravels novel mechanisms involving Cyclin E1 and MMP9 in G6PD-mediated ccRCC progression. Methods: Real-time RT-PCR, Western blot and immunohistochemistry were used to determine the expression patterns of G6PD, Cyclin E1 and MMP9 in ccRCC. TCGA dataset mining was used to identify Cyclin E1 and MMP9 correlations with G6PD expression, relationships between clinicopathological characteristics of ccRCC and the genes of interest, as well as the prognosis of ccRCC patients. The role of G6PD in ccRCC progression and the regulatory effect of G6PD on Cyclin E1 and MMP9 expression were investigated by using a series of cytological function assays in vitro. To verify this mechanism in vivo, xenografted mice models were established. Results: G6PD, Cyclin E1 and MMP9 were overexpressed and positively correlated in ccRCC, and they were associated with poor prognosis of ccRCC patients. Moreover, G6PD changed cell cycle dynamics, facilitated cells proliferation, promoted migration in vitro, and enhanced ccRCC development in vivo, more likely through enhancing Cyclin E1 and MMP9 expression. Conclusion: These findings present G6PD, Cyclin E1 and MMP9, which contribute to ccRCC progression, as novel biomarkers and potential therapeutic targets for ccRCC treatment.

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Section: Discussionmentioning

confidence: 99%

“…Clear cell renal cell carcinoma (ccRCC) is the most common and dangerous malignancy subtype derived from kidney tissue, accounting for approximately 80% of all renal cell carcinoma cases [1,2]. Globally, about 400,000 new diagnosed cases and 139,000 death cases are expected to occur per year [3].…”

Section: Introductionmentioning

confidence: 99%

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

Yang¹,

Zhang²,

Ni³

et al. 2020

Preprint

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“…Interferon, Resveratrol, Miltefosine, Perifosine, Filipin, MCD, Emodin, monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs, respectively), diets with linoleic acid, oleic acid, marine fish oils are believed to be the perturbators of the cell membrane fluidity and are utilized for cancer treatment or prevention [ 93 ]. Chloroquine or hydroxychloroquine (HCQ) is an FDA-approved inhibitor of autophagy; ROC-325, Lys05, and DQ661 are the newest most potent inhibitors of autophagy from preclinical trials [ 94 , 95 ]. Note that HALAVEN, the actin-modifying agent, prevents glioma transitions to the mesenchymal subtype induced by the hypoxic condition.…”

Section: Potential Pharmacological Modulators Of Cell Fusionmentioning

confidence: 99%

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

Filippova

Nabors

2020

Cancers

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Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.

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“…It has been shown to induce potent cytotoxic effects in VHL-deficient ccRCC cells, compared to their VHL wild-type counterparts [41]. The STF-62247-stimulated synthetic lethality occurs in a HIF-independent manner through autophagy; however, the mechanistic links between VHL and autophagy are incompletely understood [42].…”

Section: Targeting Trunk Mutationsmentioning

confidence: 99%

Targeting the Deterministic Evolutionary Trajectories of Clear Cell Renal Cell Carcinoma

Kowalewski

Zdrenka²,

Grzanka

et al. 2020

Cancers

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The emergence of clinical resistance to currently available systemic therapies forces us to rethink our approach to clear cell renal cell carcinoma (ccRCC). The ability to influence ccRCC evolution by inhibiting processes that propel it or manipulating its course may be an adequate strategy. There are seven deterministic evolutionary trajectories of ccRCC, which correlate with clinical phenotypes. We suspect that each trajectory has its own unique weaknesses that could be exploited. In this review, we have summarized recent advances in the treatment of ccRCC and demonstrated how to improve systemic therapies from the evolutionary perspective. Since there are only a few evolutionary trajectories in ccRCC, it appears feasible to use them as potential biomarkers for guiding intervention and surveillance. We believe that the presented patient stratification could help predict future steps of malignant progression, thereby informing optimal and personalized clinical decisions.

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Therapeutic Targeting of Autophagy for Renal Cell Carcinoma Therapy

Cited by 37 publications

References 90 publications

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

Targeting the Deterministic Evolutionary Trajectories of Clear Cell Renal Cell Carcinoma

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