Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance

Guerra, Flora; Bucci, Cecilia

doi:10.3390/cancers11081096

Cited by 36 publications

(32 citation statements)

References 141 publications

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“…A previous report by our group showed that RAB7A, a small GTPase and a master regulator of the late endocytic pathway, was able to modulate secretion of CD9-and CD81-positive exosomes [37]. The decreased expression of tetraspanin CD63 found in the present study may therefore be indicative of an altered late endocytic pathway [38], possibly suggesting disarrangements in late endocytic trafficking in PF&S.…”

Section: Discussionsupporting

confidence: 63%

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Picca

Beli

Calvani

et al. 2020

Cells

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Mitochondrial dysfunction and systemic inflammation are major factors in the development of sarcopenia, but the molecular determinants linking the two mechanisms are only partially understood. The study of extracellular vesicle (EV) trafficking may provide insights into this relationship. Circulating small EVs (sEVs) from serum of 11 older adults with physical frailty and sarcopenia (PF&S) and 10 controls were purified and characterized. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers, including adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2) were quantified by Western immunoblotting. Participants with PF&S showed higher levels of circulating sEVs relative to controls. Protein levels of CD9 and CD63 were lower in the sEV fraction of PF&S older adults, while CD81 was unvaried between groups. In addition, circulating sEVs from PF&S participants had lower amounts of ATP5A, NDUFS3, and SDHB. No signal was detected for MTCOI, NDUFB8, or UQCRC2 in either participant group. Our findings indicate that, in spite of increased sEV secretion, lower amounts of mitochondrial components are discarded through EV in older adults with PF&S. In-depth analysis of EV trafficking might open new venues for biomarker discovery and treatment development for PF&S.

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Section: Discussionsupporting

confidence: 63%

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Picca

Beli

Calvani

et al. 2020

Cells

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“…One molecule that is essential for the degradation of EGFR and other receptors is RAB7, which is responsible for sorting them into late endosomes and lysosomes. In agreement with the effect observed after TMEM167A downregulation in gliomas cells, it has been shown that RAB7 is essential for AKT activation and signaling in other cancer cells [30]. Moreover, there is plenty of evidences supporting the existence of a tight regulation of the spatial and temporal compartmentalization of AKT activation and function [9].…”

Section: Discussionsupporting

confidence: 68%

The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

Segura-Collar

Gargini

Tovar-Ambel

et al. 2020

Cancers

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Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular trafficking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, affecting the autophagy process and impairing EGFR trafficking and signaling. This effect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular trafficking by TMEM167A.

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“…RAB7 has also been associated with chemoresistance to cisplatin. Indeed, RAB7 was downregulated in cisplatin-resistant cervical cancer cell lines as compared to chemosensitive ones ( 107 ). Additionally, RAB7 overexpression induced chemosensitization of cisplatin-resistant cells, while depletion of RAB7 by siRNA induced resistance to cisplatin in chemosensitive cells ( 108 ).…”

Section: Impact Of Inhibiting Autophagosome-lysosome Fusion On the Rementioning

confidence: 99%

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

et al. 2021

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Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

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Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance

Cited by 36 publications

References 141 publications

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

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