Stomatin‑like protein 2 induces metastasis by regulating the expression of a rate‑limiting enzyme of the hexosamine biosynthetic pathway in pancreatic cancer

Abstract

Stomatin-like protein 2 (SLP-2) is associated with poor prognosis in several types of cancer, including pancreatic cancer (PC); however, the molecular mechanism of its involvement remains elusive. The present study aimed to elucidate the role of this protein in the development of PC. Human PC cell lines AsPC-1 and PANC-1 were transfected by a vector expressing SLP-2 shRNA. Analyses of cell proliferation, migration, invasion, chemosensitivity, and glucose uptake were conducted, while a mouse xenograft model was used to evaluate the functional role of SLP-2 in PC. Immunohistochemical analysis was retrospectively performed on human tissue samples to compare expression between the primary site (n=279) and the liver metastatic site (n=22). Furthermore, microarray analysis was conducted to identify the genes correlated with SLP-2. In vitro analysis demonstrated that cells in which SLP-2 was suppressed exhibited reduced cell motility and glucose uptake, while in vivo analysis revealed a marked decrease in the number of liver metastases. Immunohistochemistry revealed that SLP-2 was increased in liver metastatic sites. Microarray analysis indicated that this protein regulated the expression of glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway. SLP-2 contributed to the malignant character of PC by inducing liver metastasis. Cell motility and glucose uptake may be induced via the hexosamine biosynthesis pathway through the expression of GFPT2. The present study revealed a new mechanism of liver metastasis and indicated that SLP-2 and its downstream pathway could provide novel therapeutic targets for PC.

Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

“…The altered glutamine flux profiles into UDP-GlcNAc are consistent with previously proposed differences in TCA cycle flux in the D492 model on account of altered glutamine utilization following EMT (9). The increased metabolic flux observed alongside J o u r n a l P r e -p r o o f enhanced expression of GFPT2 is consistent with a mass action effect and corresponds to GFPT2's role as a biomarker for glucose uptake independent of GLUT1 (55,70). 13 C enrichment from the 5-13 C-glutamine was negligible but suggestive of flux rerouting in the TCA cycle, particularly in D492M compared to D492 and D492HER2.…”

“…Several studies have focused on the function and regulation of GFPT2 related to its role in modulating O-GlcNAcylation of proteins on account of GFPT2 in producing UDP-GlcNAc (21,22,53). GFPT2 has also been shown to counteract oxidative stress (51,69,70), although the mechanism behind that remains elusive. Our results demonstrate that GFPT2 affects protein O-GlcNAcylation, regulates the EMT program, and impacts cellular growth and invasion in a cellular subtype-specific manner in breast epithelial cells, which are consistent with the literature mentioned above.…”

“…Mitochondrial dysfunction is involved both in EMT (82) and in breast cancer (83). A recent study has connected GFPT2 to SLP-2 involved in mitochondrial regulation (70). Understanding the roles of GFPT2 in oxidative stress and H2S and mitochondrial homeostasis in mesenchymal cells is beneficial to clinical therapeutic interventions and prognostics.…”

“…The regulation of GFPT2 is inherently complex and associated with various growth factors and transcriptional regulators, including EGF, TGF-β, TNF, NF-κB, SIRT6, sXBP1, and SLP-2 etc. (53,55,56,70,84). Mutant KRAS has also been demonstrated to enhance flux into the HBP via GFPT2 that is potentiated by loss of LKB1 (74).…”

STOML2 Restricts Mitophagy and Increases Chemosensitivity in Pancreatic Cancer through Stabilizing PARL-induced PINK1 degradation

“…Stomatin-like protein 2 (STOML2 or SLP2) was primarily identi ed as a protein located in the mitochondrial inner membrane, maintaining the stability of mitochondria (8,9). Previous studies suggested that STOML2 promoted the progression of multiple malignant tumors including liver cancer (10), head and neck squamous cell carcinoma (11), ovarian cancer (12), colorectal cancer (13), and even pancreatic cancer (14). However, the relevant study in pancreatic cancer carried out by Chao et al only demonstrated the relevance of STOML2 and pancreatic cancer patients' prognosis, lacking the support of high-level clinical data such as tissue microarrays.…”