Increased expression of phospho-acetyl-CoA carboxylase protein is an independent prognostic factor for human gastric cancer without lymph node metastasis

Abstract

Upregulation of acetyl-CoA carboxylase (ACC), as a rate-limiting enzyme of fatty acid synthesis,has been recognized in multiple human cancers, implicating a critical role in cancer development and progression; yet, its role in gastric cancer still remains unclear. In the present study, we detected ACC and phosphorylated form of ACC (pACC) expression in gastric cancers and explored its clinical significance. Tissue microarray blocks containing primary gastric cancer and adjacent normal mucosa specimens obtained from 1,072 Chinese patients were used for the detection of ACC and pACC expression by immunohistochemistry. Gastric cancer cell lines were treated by metformin, and pACC was measured by Western blotting. ACC overexpression was observed in all the tumor specimens. High expression of pACC was found in 630 (58.8 %) of the 1,072 primary tumors and in 237 (66.6 %) of the 356 primary tumors without lymph node metastasis. Absent/low expression of pACC significantly correlated with advanced T stage (P < 0.001), tumor size (P = 0.010), lymph node metastasis (P < 0.001), advanced disease stage (P < 0.001), and poor histological differentiation (P = 0.014) in 1,072 primary tumors, and with advanced T stage (P = 0.015), tumor size (P = 0.017), and poor histological differentiation (P = 0.001) in 356 tumors without lymph node metastasis. Kaplan-Meier analysis showed that high expression of pACC is strongly related to better survival rates in all gastric cancer patients (P = 0.006). Cox regression analysis revealed that pACC is an independent prognostic factor only in patients without lymph node metastasis (P = 0.016). Metformin treatment leaded to increased expression of pACC, which, in turn, resulted in the reduction of cell proliferation and colony formation of gastric cancer cells (P < 0.05). Increased activation of ACC is frequent in human gastric cancer, and downregulation of pACC is an important prognostic factor, suggesting that ACC/pACC might be a potential target for cancer intervention.

Quantitative Analysis of Proteome in Non-functional Pituitary Adenomas: Clinical Relevance and Potential Benefits for the Patients

“…ACACA was traditionally recognized as target of metabolic syndrome. However, studies found that malignant tumors had a strong capability for fatty acids synthesis (53), that ACACA was overexpressed in malignant cancers, and that the inhibition of ACACA resulted in cell-cycle arrest and apoptosis of cancer cells (54,55). Thus, ACACA and some fatty acids might play important roles in cancer cell survival.…”

Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus

“…Metformin may also specifically inhibit gastric cancer cell proliferation in both in vitro and in vivo studies [ 53 ]. It inhibits the proliferation of gastric cancer cell lines by blocking cell cycle through the inhibition of cyclins [ 53 ], by increasing the expression of phospho-acetyl-CoA carboxylase protein [ 54 ], and by inhibiting a gastric cancer-related gene hepatocyte nuclear factor-4α [ 55 ]. Metformin may also induce apoptosis in human gastric cancer cells via the inhibition of survivin mediated by mTOR through the activation of AMPK [ 56 ] or via the inhibition of hypoxia inducible factor 1α and pyruvate kinase M2 signaling pathway [ 57 ].…”

Downregulation of HADH promotes gastric cancer progression via Akt signaling pathway

“…Proliferating cancer cells require lipid for cellular membrane synthesis and other essential functions [ 1 ]. Numerous studies have shown that the expression of enzymes involved in fatty acid synthesis is increased in gastric cancer (GC)[ 2 – 6 ]. However, the role of fatty acid breakdown in cancer cells remains controversial.…”