α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells

Abstract

PTEN dephosphorylates the 3-position phosphate of phosphatidylinositol 3,4,5 triphosphate (PIP(3)), thereby inhibiting AKT activation. Although attenuation of PTEN function has a major role in tumourigenesis, the underlying mechanisms remain unclear. Here we show that α-mannosidase 2C1 (MAN2C1) inhibits PTEN function in prostate cancer (PC) cells and is associated with a reduction in PTEN function in primary PC. MAN2C1 activates AKT and promotes the formation of PTEN-positive DU145 cell-derived xenograft tumours by imparing endogenous PTEN function. In 659 PC patients who were examined, ~60% of tumours were PTEN positive with elevated AKT activation. Of these, 80% display MAN2C1 overexpression that co-localizes with PTEN. Increases in MAN2C1 were detected only in PTEN-positive prostatic intraepithelial neoplasia and carcinomas, and showed a significant association with PC recurrence only in patients with PTEN-positive PCs. Mechanistically, MAN2C1 binds PTEN thereby inhibiting its PIP(3) phosphatase activity. These findings show that MAN2C1 function as a PTEN-negative regulator in PC cells.

Dual Functions for Cytosolic α-Mannosidase (Man2C1)

“…8). Consistent with this result, we found that an N-terminal fragment of Man2C1 did not have anti-apoptotic activity; notably, this fragment was previously shown to be enough to inhibit the PIP3 phosphatase activity of PTEN (20). Currently, the role of PTEN, if any, in inducing apoptosis upon Man2C1 knockdown remains unknown.…”

“…Man2C1 was recently identified as a PTEN-binding protein (20). He et al (20) suggest that Man2C1, by binding to PTEN, attenuates PTEN functions; thus, Man2C1 up-regulation could promote tumorigenesis in prostate cancer cells.…”

“…Overexpression and suppression of the Man2C1 gene each reportedly have multiple phenotypic consequences. In one investigation, transgene expression of Man2C1 promoted tumor progress in mice (18); later it was found that Man2C1 overexpression could attenuate PTEN function in prostate cancer cells (20). Con- relative to control subjects (43).…”

Accumulation of Free Oligosaccharides and Tissue Damage in Cytosolic α-Mannosidase (Man2c1)-deficient Mice

“…MAN2C1 overexpression promoted tumor growth and metastasis of xenograft tumors in immunocompromised mice. Moreover, up-regulation of MAN2C1 was observed in human prostate cancer cells, where MAN2C1 seemed to attenuate PTEN functions by binding to PTEN (19). Conversely, down-regulation of MAN2C1 induced growth delay or arrest in nasopharyngeal carcinoma cells (41) and led to mitotic arrest and apoptosis in esophageal cancer cells (20).…”

“…Indeed, this protein seems to promote the tumorigenesis in human prostate cancer cells by activating the AKT pathway as a result of PTEN-negative regulation (19). Moreover, the suppression of MAN2C1 expression resulted in mitotic arrest and apoptosis of esophageal carcinoma cells in vitro (20).…”