LHPP suppresses proliferation, migration, and invasion and promotes apoptosis in pancreatic cancer

Abstract

Pancreatic cancer (PaCa) is a common malignant tumor of the digestive system with poor prognosis and no ideal treatment for inoperable patients, which is partly due to delayed diagnoses. It is recently reported that the protein histidine phosphatase LHPP is a tumor suppressor in hepatocellular carcinoma, cervical cancer, and bladder cancer. So far, there is no study on the expression level of LHPP in PaCa, and its mechanism of action on tumors is unclear. In this experiment, LHPP expression was lower in cancer tissues than that in normal pancreatic tissue, and clinicopathological results showed that LHPP expression was correlated with the degree of differentiation and lymphatic metastasis of pancreatic carcinoma. The biological characteristics of LHPP in PaCa cells were examined by the cell counting kit-8 assay, transwell assay, and monoclonal formation test. The inhibitory mechanism of LHPP in PaCa cells was determined using Western blotting and flow cytometry. The results showed that LHPP restrained PaCa cell proliferation, migration, and invasion. Increased LHPP expression promoted the apoptosis of PaCa cells through higher activation of cleaved-PARP and cleaved-Casp3 and lower activation of cIAP1. Importantly, the increase in LHPP enhanced PTEN expression and decreased the phosphorylated AKT level. Moreover, LHPP-induced apoptosis was diminished by SC79 (AKT activator) in PaCa cells. In conclusion, LHPP blocks proliferation, migration, and invasion and enhances apoptosis in PaCa cells through the PTEN/AKT signaling pathway.

LHPP Inhibits the Proliferation and Metastasis of Renal Cell Carcinoma

“…In bladder cancer, LHPP inhibits cell growth in vitro and in vivo via regulating the AKT/p65 signaling pathway [14]. In pancreatic cancer, LHPP suppresses cell proliferation and metastasis and promotes cell apoptosis via interacting with the PTEN/AKT signaling pathway [15]. However, the biological function of LHPP in RCC remains unknown.…”

LHPP suppresses colorectal cancer cell migration and invasion in vitro and in vivo by inhibiting Smad3 phosphorylation in the TGF-β pathway

“…LHPP reduction promoted bladder cancer cell proliferation and growth by mediating the AKT/p65 signaling pathway [ 18 ]. In pancreatic cancer, enhanced LHPP expression restored PTEN protein and repressed the AKT phosphorylation resulted to inhibition of PaCa (Pancreatic cancer) progression and metastasis [ 17 ]. Wang et al [ 19 ] illustrated that LHPP could not only repress aggressive phenotype but also trigger autophagy in papillary thyroid cancer.…”

“…Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) , a type of histidine phosphatase protein, has been proven as a tumor suppressor in hepatocellular carcinoma [ 15 ] (HCC), cervical [ 16 ], pancreatic [ 17 ], bladder [ 18 ], and thyroid cancers [ 19 ] by regulating the AKT signaling pathway. In the previous research [ 20 ], LHPP protein overexpression was highly related to better prognosis and lower tumor–node–metastasis classification of patients with CRC.…”

NME/NM23/NDPK and Histidine Phosphorylation

“…acts as a tumor suppressor in liver cancer where its expression is downregulated, whereas pNME1/2 are upregulated, resulting in increased histidine phosphorylation of proteins [126]. Other studies in colorectal [127], bladder [128], pancreatic [129], thyroid [130] and cervical cancer [131] have demonstrated that LHPP. is downregulated in cancer [132].…”