The Fhit protein: an opportunity to overcome chemoresistance

Gaudio, Eugenio; Paduano, Francesco; Croce, Carlo M.; Trapasso, Francesco

doi:10.18632/aging.101123

Cited by 4 publications

(6 citation statements)

References 27 publications

(30 reference statements)

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“…Lung tumour cells are sensitive to treatments based on selective inhibitors of oxidative phosphorylation that act on the mitochondrial complex III, while these are ineffective when FHIT is present. erefore, an assessment of HSP60/HSP10 levels (in association with the expression of FHIT) appears fundamental in choosing the kind of therapy to be used against lung cancer [65][66][67][68][69] (Figure 1). target molecules are toll-like receptors, in particular TLR-4 and TLR-2.…”

Section: Fragile Histidine Triad (Fhit) Proteinmentioning

confidence: 99%

Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors?

Fucarino

Pitruzzella

2020

Journal of Oncology

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Cancers are one of the major challenges faced by modern medicine both because of their impact in terms of the amount of cases and of the ineffectiveness of therapies used today. A concrete support to the fight against them can be found in the analysis and understanding of the molecular mechanisms involving molecular chaperones. In particular, HSP60 and HSP10 seem to play an important role in carcinogenesis, supporting tumours in their proliferation, survival, and metastasis. Efforts must be directed toward finding ways to eliminate or block this “mistaken” chaperone. Therefore, the scientific community must develop therapeutic strategies that consider HSP60 and HSP10 as the possible target of an anti-tumoural treatment and not only as diagnostic biomarkers, since they contribute to the evolution of pre-cancerous respiratory pathologies in lung tumours. HSP60 acts at the mitochondrial, cytoplasmic, and extracellular levels in the development of cancer pathologies. The molecular mechanisms in which these chaperones are involved concern cell survival, the restoration of a condition of absence of replicative senescence, the promotion of pro-inflammatory environments, and an increase in the ability to form metastases. In this review, we will also present examples of interactions between HSP60 and HSP10 and different molecules and ways to exploit this knowledge in anticancer therapies for lung tumours. In order to improve not only chances for an earlier diagnosis but also treatments for patients suffering from this type of disease, chaperones must be considered as key agents in carcinogenesis and primary targets in therapeutics.

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Section: Fragile Histidine Triad (Fhit) Proteinmentioning

confidence: 99%

Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors?

Fucarino

Pitruzzella

2020

Journal of Oncology

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“…Only more than a decade after its identification has our group identified a list of Fhit candidate partners, including among them, FRDX, HSP10 [ 4 ], and annexin A4 (A4) [ 5 ]. We also identified a short 7-aminoacids peptide from the Fhit protein that is still able to bind A4 and sensitize lung cancer cells to paclitaxel, thus recapitulating the activity of the full-length Fhit protein on A4 [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Tumour Suppressor Fhit Protein Activates C-Raf Ubiquitination and Degradation in Human Melanoma Cells by Interacting with Hsp90

Paduano

Gaudio²,

Trapasso³

2022

Biomedicines

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Fhit protein expression is reduced in the majority of human tumors; moreover, its restoration both triggers apoptosis of cancer cells and suppresses tumor formation in a large number of preclinical models of cancers. In the following study, we observed that Fhit expression is significantly reduced in human melanoma cells, and their in vivo growth is blocked by a recombinant adenovirus carrying the FHIT gene. Importantly, we found here that Fhit physically interacts with Hsp90. Since Hsp90 is a chaperone with a crucial function in the conformational maturation and stabilization of C-Raf, we also investigated whether Fhit could interfere with the Hsp90/C-Raf protein complex in melanoma. Interestingly, the administration of the Hsp90 inhibitor 17-AAG, in combination with Fhit protein overexpression in melanoma cells, reacts synergistically to increase C-Raf ubiquitination and degradation. These data reveal Hsp90 as a novel interactor of Fhit and suggest that FHIT activity restoration could represent a helpful strategy for suppressing the oncogenic C-Raf pathway in the therapy of human melanoma.

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“…3,4 The restoration of FHIT in these cancerous cells suppresses tumorigenicity, induces cell-cycle arrest, increases the proapoptotic (Bax, Bad, and Bid), and lowers the level of Bcl-2 family (Bcl-2, Bcl-XL , and Mcl-1) [5][6][7] ; thus, FHIT gene therapy could be a new therapeutic approach for cancer treatment. 8 Many agents such as UV irradiation, alkylation of bases, chemotherapy, and oxidative stress are involved in DNA damage. 9 Etoposide, an inhibitor of topoisomerase II, is used in chemotherapy of cancer by inducing DNA damage and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, it has been shown the lack of FHIT expression or function in cancer cells has been correlated with the initiation and/or progression of tumors . The restoration of FHIT in these cancerous cells suppresses tumorigenicity, induces cell‐cycle arrest, increases the proapoptotic (Bax, Bad, and Bid), and lowers the level of Bcl‐2 family (Bcl‐2, Bcl‐ XL , and Mcl‐1); thus, FHIT gene therapy could be a new therapeutic approach for cancer treatment …”

Section: Introductionmentioning

confidence: 99%

Signaling Crosstalk of FHIT, p53, and p38 in etoposide‐induced apoptosis in MCF‐7 cells

Khedri

Khaghani

Kheirollah

et al. 2019

J of Cellular Biochemistry

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Fragile histidine trail (FHIT) is a tumor suppressor in response to DNA damage which has been deleted in various tumors. However, the signaling mechanisms and interactions of FHIT with regard to apoptotic proteins including p53 and p38 in the DNA damage-induced apoptosis are not well described. In the present study, we used etoposide-induced DNA damage in MCF-7 as a model to address these crosstalks. The time course study showed that the expression of FHIT, p53, and p38MAPK started after 1 hour following etoposide treatment. FHIT overexpression led to increase p53 expression, p38 activation, and augmented apoptosis following etoposide-induced DNA damage compared to wild-type cells. However, FHIT knockdown blocked p53 expression, delayed p38 activation, and completely inhibited etoposide-induced apoptosis. Inhibition of p38 activity prevented induction of p53, FHIT, and apoptosis in this model. Thus, activation of p38 upon etoposide treatment leads to increase in FHIT and p53 expression. In p53 knockdown MCF-7, the FHIT induction was hampered but p38 activation was induced in lower doses of etoposide. In p53 knockdown cells, inhibition of p38 induced FHIT expression and apoptosis. Our data demonstrated that the exposure of MCF-7 cells to etoposide increases apoptosis through a mechanism involving the activation of the p38-FHIT-p53 pathway. Moreover, our findings suggest signaling interaction for these pathways may represent a promising therapy for breast cancer. K E Y W O R D S DNA damage, etoposide, FHIT, p38, p53 J Cell Biochem. 2019;120:9125-9137.wileyonlinelibrary.com/journal/jcb

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The Fhit protein: an opportunity to overcome chemoresistance

Cited by 4 publications

References 27 publications

Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors?

Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors?

The Tumour Suppressor Fhit Protein Activates C-Raf Ubiquitination and Degradation in Human Melanoma Cells by Interacting with Hsp90

Signaling Crosstalk of FHIT, p53, and p38 in etoposide‐induced apoptosis in MCF‐7 cells

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