Abstract
Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal-as well as midregion-and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy.
Highlights
IntroductionParathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is the product of a gene spanning more than 15 kb of genomic
PTHrP is a Multidomain and Multifunctional ProteinParathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is the product of a gene spanning more than 15 kb of genomicDNA and exhibiting a complex organization in humans, where it generates multiple mRNA variants through alternative splicing events and utilization of different promoters
Cell treatment with PTHrP antisense oligonucleotides resulted in a drastic decrease of cell proliferation and in the activation of the apoptotic program with an increase of Fas and caspase 3 transcription rates, Bax/Bcl-2 ratio and intracellular Ca++ levels. This suggested that PTHrP could promote tumor growth, protecting cells from apoptosis, and, in addition, that it could be taken into consideration as a possible target for antisense strategy aimed to the control of medulloblastoma development
Summary
Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is the product of a gene spanning more than 15 kb of genomic. Midregion PTHrP has been shown to exert effects in malignant tissues [2], which will be discussed in greater detail later It is widely-acknowledged that midregion PTHrP possesses a lysine/arginine-rich bipartite sequence, encompassing amino acids 87–107, which is homologous to the nuclear/nucleolar targeting signal (NTS) present in SV40 large tumor antigen, able to direct importin /Ran GTPase-mediated import thereby allowing the peptide to play the so-called “intracrine” role that supplements the “autocrine/paracrine” one. One of the original tumors from which PTHrP was purified and sequenced, because of the elevated concentration of its circulating form, was breast cancer [8,9] and it is well-known that PTHrP exerts multiple effects on different neoplastic cytotypes via cytosolic and nuclear targets, thereby participating to initiate and promote tumor growth and dissemination [10]. The present mini-review is focused on the role of PTHrP as a life/death regulator in animal and human tumor cell models, with particular interest on the biochemical and molecular mechanisms involved, providing some examples of present and potential utilization of
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
