The Fhit protein: an opportunity to overcome chemoresistance

the FHIT (Fragile Histidine Triad) gene product appeared as a very intriguing molecule to be investigated in the pathogenesis of cancer. In fact, FHIT encompasses the most common fragile site in human [2], whose genetic alterations, leading to the loss of FHIT expression, have been reported in the majority of human cancers [3]. Other than genetic lesions, FHIT expression in both solid and hematopoietic malignancies is also impaired by its promoter hypermethylation [4, 5], making Fhit protein virtually completely lost in tumors. Moreover, several reports have intriguingly pointed to Fhit loss as a very early event in epithelial tumorigenesis (presumably, the earliest event in smoking-related lung cancer) [3]. These findings, along with both chemically induced and spontaneous predisposition to cancer development of Fhit+/-and Fhit-/-mice, respectively [6, 7], have encouraged the application of a gene therapy approach in several experimental models of cancer, both in vitro and in vivo. We successfully demonstrated that Fhit restoration in cancer cells through recombinant adeno-or adenoassociate viruses was able to trigger apoptosis in a number of cancer types, including esophageal, pancreatic, mammary cancer, and even leukemia, and to block their in vivo tumor formation [8-11]. Moreover, Fhit protein was not only curative in Fhit+/-mice bearing NMBA-induced forestomach tumors [12] but it could also prevent tumor formation in Fhit+/-mice treated with the same carcinogen [13, 14]. These results were very interesting as they represented the proof-of-principle that FHIT was a therapeutic gene indeed. Fhit protein function is still partly a mystery; for long time we only knew that it was an enzyme belonging to the HIT (Histidine Triad) protein family, a class of molecules involved in the hydrolysis of dinucleoside three-and tetraphosphate [3]. In order to investigate the role of Fhit hydrolase activity in tumor suppression, we planned an apoptosis quantitative assay based on the design of FHIT alleles driven by recombinant adenoviruses. We proved that the Fhit mutants able to bind the substrate but with impaired catalytic activity could still efficiently trigger apoptosis of cancer cells; also, apoptosis was still observed with Fhit mutants unable to bind the substrate, even though to a much lower extent compared to the wild-type protein [15, 16], Letter to the Editors thus suggesting that Fhit tumor suppression activity in cancer cells could presumably be dependent by different and independent molecular pathways. However, because of the failure to identify protein partners through conventional approaches, no Fhit pathways have ever been …