GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer

Abstract

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in multiple solid tumor types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Integrative analysis of the region identifies a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to TOR signaling. Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. Thus, reinforcing genomic and genetic, biological, functional and biochemical data in yeast and humans establish GOLPH3 as a novel oncogene that is commonly targeted for amplification in human cancer and capable of modulating the response to rapamycin, a cancer drug in clinical use.

GOLPH3, a Good Prognostic Indicator in Early-stage NSCLC Related to Tumor Angiogenesis

“…And it has been reported that overexpression of GOLPH3 promotes cell transformation via enhancing the activity of the serine/threonine kinase mTOR. Recent studies have found that the development of a variety of solid tumors abnormally activation is related with mTOR signal transduction pathways in breast cancer, glioma and so on, so the GOLPH3 has become an important target for cancer therapy (Guertin et al, 2007;Scott et al, 2009). However, few studies have investigated the expression and significance of GOLPH3 in earlystage NSCC, especially for the prognosis of early-stage NSCLC.…”

“…GOLPH3 localizes in human chromosome 5p13, a region that is requently amplified in multiple solid tumor types (Bohm et al, 2002;Yokoi et al, 2002;Gorringe et al, 2005). Simultaneously, GOLPH3 is highly expressed in several solid tumors, including melanoma, colon adenocarcinoma, breast cancer and non-small cell lung cancer (Scott et al, 2009;Zeng et al, 2012). Recently, GOLPH3 has been shown to be involved in tumorigenesis by activating mTOR signaling, enhancing AKT activity, as well as decreasing FOXO1 transcriptional activity (Zeng et al, 2012).…”

An Oncogenic Protein Golgi Phosphoprotein 3 Up-regulates Cell Migration via Sialylation

“…The Gateway TM entry vectors were constructed as follows. The cDNA of HA-tagged GOLPH3 (a generous gift from Dr. Lynda Chin, Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center) (21) and HA-tagged, shRNA resistance GOLPH3 were cloned by standard PCR protocols, into pENTR/D-TOPO (Invitrogen). The overlap extension PCRs were used to construct GOLPH3 mutants, which lacks a tetramer formation (⌬190 -201) (28) or the binding to PI4P (R171A/R174A and W81A/R90A) (29).…”

“…Recently, a Golgi phosphoprotein 3 (GOLPH3) was identified as an oncogenic protein in human solid tumors such as lung cancer, breast cancer, colon cancer, and melanoma, localized on the peripheral membrane of the trans-Golgi network and modulating a mammalian target of rapamycin (mTOR) signaling (21), budding of vesicles from the trans-Golgi, and recycling of transmembrane receptors (22). It is worth noting that the expression levels of GOLPH3 are highly related to the clinical stages of breast (23), esophageal (24), and lung (21) cancers and glioblastoma (25). The homolog of yeast GOLPH3, VSP74, is reportedly involved in the retention of mannosyltransferases at the Golgi, knockout of which results in the production of hypoglycosylated proteins (26).…”

Lentivirus Mediated GOLPH3 shRNA Inhibits Growth and Metastasis of Esophageal Squamous Cancer

“…Recently, Golgi phosphoprotein 3 (GOLPH3) has been demonstrated as a novel oncogene involved in the development of cancer of the lung, breast, ovary, prostate, colon, melanoma, rhabdomyosarcoma and glioma (Romanuik et al, 2009;Scott et al, 2009;Kunigou et al, 2011;Li et al, 2011). GOLPH3 was initially detected as a phosphorylated protein localized to the Golgi apparatus (Dippold et al, 2009;Scott and Chin 2010).…”