Down-regulation of LHPP in cervical cancer influences cell proliferation, metastasis and apoptosis by modulating AKT.

ABSTRACT

Cervical cancer is a leading severe malignancy throughout the world. Though various pathologies associated with cervical cancer progression have been demonstrated, further study is still necessary to reveal the tumorigenesis of cervical cancer. The protein histidine phosphatase LHPP is reported as a tumor suppressor. Histidine phosphorylation, also known as hidden phosphoproteome, is a poorly characterized post-translational modification of proteins. LHPP is evolutionarily conserved from worm to human. In the present study, we discovered that LHPP expression levels were lower in human cervical cancer tumors than that in adjacent normal tissue samples. LHPP expression levels were also reduced in several cervical cancer cell lines. Further, LHPP over-expression reduced the cell proliferation, migration and invasion, associated with the change of p53 and metastasis signaling pathways. Moreover, over-expressing LHPP markedly induced apoptosis in human cervical cancer cells via promoting the cleaved Caspse-3 and PARP. Importantly, we found that LHPP over-expression blocked AKT activation. Elevating AKT activity could abolish the role of LHPP over-expression in reducing cell proliferation and metastasis, as well as in inducing apoptotic response. Moreover, suppressing p53 expression with its inhibitor of PFTα abrogated the activity of LHPP to impede cell proliferation and metastasis, and to trigger apoptosis. AKT phosphorylation also restrained p53 expression levels in cervical cancer cells. In vivo, the anti-cervical cancer effects of LJPP were verified, which were also via the repression of cell proliferation and metastasis, and the induction of apoptosis. Therefore, LHPP could be considered as an effective candidate to develop effective therapeutic strategy against cervical cancer development.