Parathyroid hormone-related protein confers chemoresistance by blocking apoptosis signaling via death receptors and mitochondria

Parathyroid hormone (PTH) has a central role in the regulation of serum calcium and phosphate, whereas parathyroid hormone-related peptide (PTHrP) has important developmental roles. In addition, PTHrP has been discovered as a causative agent of hypercalcemia of malignancy. PTHrP is also expressed in many tumors, and expression often correlates with unfavorable prognosis. We have investigated the effects of PTHrP on apoptosis signaling pathways initiated by DNA damaging chemotherapeutic drugs. Stimulation experiments of the CD95-, the TNF-R-, and the TRAIL-R-death receptor systems in Saos human osteosarcoma cells revealed that PTHrP can block signaling via each of these death receptors. Furthermore, our findings demonstrate a link between PTHrP and the mitochondrial apoptosis pathway. PTHrP down-regulates expression of pro-apoptotic Bcl-2 family members like Bax and PUMA and up-regulates expression of antiapoptotic molecules like Bcl-2 and Bcl-xl. It is of clinical relevance that PTHrP and anticancer drugs show opposing interactions on death receptor-triggered as well as on mitochondrial apoptosis pathways. In addition, PTHrP induces chemoresistance by interference with p53 family-dependent apoptosis signaling pathways and p53-mediated transactivation of apoptosis target genes. Inhibition of CD95- and Bax gene transactivation is a mechanism by which PTHrP reduced the apoptosis response and treatment sensitivity of tumor cells. Our data indicate that PTHrP inhibits major apoptosis signaling pathways by blocking signaling via p53, death receptors and mitochondria and, consequently, confers chemoresistance of cancer cells. Thus, beyond its importance in development and differentiation, we describe an important role for PTHrP in tumorigenesis.