Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear.MethodsATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays.ResultsHere, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells.ConclusionTaken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling.Electronic supplementary materialThe online version of this article (10.1186/s12964-017-0208-8) contains supplementary material, which is available to authorized users.

Identification of an Autophagy-Related Gene Signature that Can Improve Prognosis of Hepatocellular Carcinoma Patients

“…Indeed, suppression of ATIC expression significantly inhibited the ability of HCC cells to proliferate and migrate through the regulation of the AMPK-mTOR-S6K1 signaling pathway. Therefore, in line with our results, the high expression of ATIC could be positively correlated with adverse prognosis in HCC patients [33].…”

Development of an autophagy-related gene prognostic signature in lung adenocarcinoma and lung squamous cell carcinoma

“…We also encourage multi-center data to confirm our findings. More laboratory data based on the the mTOR signaling pathway inhibit EIF4E complex and the cap-dependent translation to regulate mRNA translation promote or inhibit the development of tumors as a bifunctional factor/ associate with poor prognosis in breast cancer (Karlsson et al, 2011)/ act as tumor suppressor in SCC (Spilka et al, 2012) TP63 the multiple isoforms of the p63 transcription factor the metabolic pathways, like glucose metabolism, activation of TIGAR and HK II, degradation of PGM, fatty acid oxidation and mitochondrial respiration (Maddocks & Vousden, 2011) activate the autophagy gene network tumorigenesis and tumor suppression/ relate to the oncogenic potential role of SCC/ the genetic variant rs10937405 in TP63 have been found in various ethnic populations like Japanese, Korea, north Indian and British (Wang et al, 2011) population and to be associated with the lung cancer risk BNIP3 a proapoptotic protein belongs to the Bcl-2 family the mitochondrial dysfunction/ the production of ROS/ the repression of mTOR regulate programmed cell death and impart the prodeath activity/ induce autophagy a progression marker in primary human breast cancer/ be linked with poor OS in NSCLC ATIC a cytosolic enzyme in the de novo purine biosynthetic pathway the production of the intermediate FAICAR and IMP (Chan et al, 2015;Greasley et al, 2001) unknown play a significant role in the antitumorigenic effects in the drug of NSCLC/ be related to the poor prognosis of HCC (Jiang et al, 2019;Li et al, 2017) ERO1A a major regulator of PDI PDI dysfunction/ unfolded protein response/ ER stress participate in tumorigenesis a marker of poor prognosis in some tumors, such as glioblastoma, breast cancer and hepatocellular carcinoma/ a poor prognostic factor for OS in NSCLC (Kim et al, 2018) (continued on next page)…”

Fermentable fiber-induced hepatocellular carcinoma in mice recapitulates gene signatures found in human liver cancer

“…We observed that genes involved in cell-cell adhesion (ATIC, RUVBL1, ANXA2, BZW2 and TAGLN2) and cell division (RUVBL1, CCNB1 and DYNLT1) were significantly over-expressed in human HCC and associated with poor patient survival. Both ATIC and BZW2 are considered human oncogenic genes that promote cancer proliferation and migration through mTOR signaling [53,54]. Comparatively, TAGLN2 is known as a tumor suppressor whose protective effects are inhibited when phosphorylated by a cdc2-related serine/threonine protein kinase [55].…”