Autophagy as a Vital Therapy Target for Renal Cell Carcinoma

He, Yinghua; Tian, Guo

doi:10.3389/fphar.2020.518225

Cited by 11 publications

(9 citation statements)

References 73 publications

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“…Autophagy is an essential procedure in the biological function accomplishment of ccRCC [ 24 ]. The autophagy-related genes, signaling pathways, and markers are associated with ccRCC, and to further analyze the inner link between autophagy molecules to clarify conversion between autophagy and apoptosis, they can provide new ways for an early diagnosis on ccRCC and provide novel strategy to clinical treatment [ 10 , 24 , 25 ]. In this study, large-scale gene expression profile was paged for the investigation on the association within autophagy-related genes and clinicopathological characteristics, as well as OS in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TP53INP2 Promotes Apoptosis in Clear Cell Renal Cell Cancer via Caspase-8/TRAF6 Signaling Pathway

Liu

et al. 2022

Journal of Immunology Research

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Clear cell renal cell cancer (ccRCC) is a tumor of high malignancy, which can escape apoptosis. The tumor protein p53-inducible nuclear protein 2 (TP53INP2), known as an autophagy protein, is the essential part for autophagosome formation and sensitizes cells to apoptosis. Our study is aimed at exploring the role of TP53INP2 in ccRCC. We have identified the autophagy-related genes (ARGs) of differential expression in ccRCC patients with the help of the TCGA database by bioinformatics analysis. Our assays of quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were for the determination on the both levels of mRNA and protein. Overexpression of TP53INP2 on cellular proliferation, migration, and apoptosis of ccRCC was verified in the ways of performing CCK-8, wound scrape, transwell and flow cytometry assays in vitro, and a mice tumor model in vivo. Transmission electron microscopy was used to measure autophagy formation. The underlying mechanisms of TP53INP2 on ccRCC were determined via coimmunoprecipitation. TP53INP2 was found highly associated with an outcome of worse overall survival (OS) in Kaplan-Meier curves, and this parameter in ccRCC tissues was also lower than the normal tissues. Overexpression of TP53INP2 inhibited ccRCC cellular proliferation, migration, and invasion, as well as the tumor growth of mice. Those cells treated with autophagy inhibitor chloroquine (CQ) or TP53INP2 increased the apoptosis rate. TP53INP2 promoted autophagy formation and elevated the ratio of LC3 II/LC3 I. However, TP53INP2 did not significantly decrease the p-mTOR level. In addition, TP53INP2 activates the expressions of caspase-3, caspase-8, and PARP. Caspase-8 and TNF receptor associated factor 6 (TRAF6) were found to bind to each other in the presence of TP53INP2. TP53INP2 induces apoptosis in ccRCC cells through caspase-8/TRAF6 pathway, rather than the autophagy-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Overexpression of TP53INP2 Promotes Apoptosis in Clear Cell Renal Cell Cancer via Caspase-8/TRAF6 Signaling Pathway

Liu

et al. 2022

Journal of Immunology Research

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“…Autophagy has been reported to be either inhibiting or promoting tumor progression by changing the malignant behavior of tumor cells, implying it is a very important mechanism for cell invasion and metastasis, angiogenesis, or tumorigenesis. In other words, it is suggested that lack of autophagy in tumor cells causes tumor suppression or tumorigenesis through different mechanisms [ 11 , 33 , 34 ]. Interferons (IFNs) induce the expression of interferon-stimulated genes (ISGs) and play a critical role in innate immune response against numerous viral infections by inhibiting autophagy [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

IFI35 Promotes Renal Cancer Progression by Inhibiting pSTAT1/pSTAT6-Dependent Autophagy

Chai

Shi

Sobhani

et al. 2022

Cancers

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Interferon-induced protein 35 (IFI35), is currently acknowledged to govern the virus-related immune inflammatory responses. However, the biological significance and function of IFI35 in renal cell cancer (RCC) is still not well understood. Here, IFI35 expression and function were investigated in RCC tissues, renal cancer cells, and animal models. The results showed that IFI35 expression was significantly increased in 200 specimens of RCC patients. We found that higher IFI35 levels were significantly correlated with poor RCC prognosis. In human cell lines, the knockdown of IFI35 suppressed the malignant behavior of renal cancer cells. Similarly, the IFI35 knockdown resulted in significant inhibition of tumor progression in the subcutaneous or lung metastasis mouse model. Furthermore, the knockdown of IFI35 promoted the induction of autophagy by enhancing the autophagy-related gene expression (LC3-II, Beclin-1, and ATG-5). Additionally, blockade of STAT1/STAT6 phosphorylation (pSTAT1/pSTAT6) abrogated the induced autophagy by IFI35 knockdown in renal cancer cells. The autophagy inhibitor 3-MA also abolished the prevention of tumor growth by deleting IFI35 in renal cancer models. The above results suggest that the knockdown of IFI35 suppressed tumor progression of renal cancer by pSTAT1/pSTAT6-dependent autophagy. Our research revealed that IFI35 may serve as a potential diagnosis and therapeutic target for RCC.

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“…The role of autophagy in renal cancer is not yet fully explained. While some in vivo studies demonstrated that the induction of autophagy is capable of activating apoptosis in precancerous cells, other authors argue that the intensification of autophagy during chemotherapy may facilitate tumor survival and hence accelerate tumor progression [ 67 , 68 , 69 , 70 ]. Despite its dual role in carcinogenesis, autophagy has been recently suggested as a therapeutic target for renal cancer [ 4 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

“…While some in vivo studies demonstrated that the induction of autophagy is capable of activating apoptosis in precancerous cells, other authors argue that the intensification of autophagy during chemotherapy may facilitate tumor survival and hence accelerate tumor progression [ 67 , 68 , 69 , 70 ]. Despite its dual role in carcinogenesis, autophagy has been recently suggested as a therapeutic target for renal cancer [ 4 , 69 ]. The rationale is based on the fact that RCC cells exhibit an elevated basal level of autophagy, can alleviate periods of therapy-induced stress, and promote drug and radiation resistance [ 66 , 71 ] ( Figure 8 ).…”

Section: Discussionmentioning

confidence: 99%

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma

Kowalewski

Jaworski

Borowczak

et al. 2022

IJMS

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Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p < 0.05). We found a positive correlation between expressions of TOLLIP in the primary tumor and its metastases (p < 0.05; k = 0.48). TOLLIP expression significantly correlates with a lower overall survival rate (p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy.

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Autophagy as a Vital Therapy Target for Renal Cell Carcinoma

Cited by 11 publications

References 73 publications

Overexpression of TP53INP2 Promotes Apoptosis in Clear Cell Renal Cell Cancer via Caspase-8/TRAF6 Signaling Pathway

Overexpression of TP53INP2 Promotes Apoptosis in Clear Cell Renal Cell Cancer via Caspase-8/TRAF6 Signaling Pathway

IFI35 Promotes Renal Cancer Progression by Inhibiting pSTAT1/pSTAT6-Dependent Autophagy

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma

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