Lipin‐1 determines lung cancer cell survival and chemotherapy sensitivity by regulation of endoplasmic reticulum homeostasis and autophagy

Abstract

Cancer cells undergo comprehensive metabolic reprogramming to meet the increased requirements of energy and building blocks for proliferation. Lipin‐1, a phosphatidic acid phosphatase converting phosphatidic acid (PA) to diacylglycerol (DAG), is upregulated in lung adenocarcinoma (LUAD) cell lines and tumor tissues. In this study, we reveal high lipin‐1 expression is correlated with poor prognosis of patients with LUAD. Knockdown of lipin‐1 decreases cell viability and proliferation in LUAD cells, whereas it has less effect on nontumorigenic lung cells. Autophagy and ER stress play important roles in tumor initiation and progression. Lipin‐1 knockdown induces the initiation of autophagy while disrupts formation of autolysosome. Lipin‐1 silencing induces the activation of ER stress through the IRE1α pathway. Furthermore, we demonstrate disrupted ER homeostasis contributes to the cell phenotype, and the elevated autophagy initiation is due to the ER stress in part. For the first time, we show lack of lipin‐1 enhances the sensitivity of LUAD cells to cisplatin treatment. Our results suggest that lipin‐1 is a potential target, alone or combined with other treatment, for lung cancer therapy.

Long noncoding RNA growth arrest‐specific 5 facilitates glioma cell sensitivity to cisplatin by suppressing excessive autophagy in an mTOR‐dependent manner

“…Conversely, U138 cells that had a relatively low expression of GAS5 exhibited less resistance to cisplatin after GAS5 elevation. 25 Consistent with our finding in the current study, treatment with cisplatin increased autophagy in glioma cells. Analogous with our results, knockdown of GAS5 causes tamoxifen resistance and reduces the chemotherapeutic effect of dendrosomal curcumin in breast cancer cells.…”

“…13,20 Intriguingly, previous findings substantiated the correlation between high levels of GAS5 and increased the probability of 2-year overall survival in patients with glioblastoma. 24,25 For instance, CD24 contributes to sorafenib resistance via activating autophagy in hepatocellular carcinoma. Conversely, U138 cells that had a relatively low expression of GAS5 exhibited less resistance to cisplatin after GAS5 elevation.…”

Expression and clinicopathological significance of lipin‐1 in human breast cancer and its association with p53 tumor suppressor gene

“…Furthermore, lipin‐1 expression was significantly associated with good prognosis in patients with BC regardless of BC status including ER‐positive, ER‐negative, PR‐negative, HER2‐ positive, lymph node‐positive, and lymph node‐negative. However, although results obtained from Kaplan–Meier Plotter and data set of breast cancer confirms our findings, some studies have shown a correlation between high LPIN1 expression with worse prognosis in patients with basal‐like TNBC (He et al, 2017) and lung adenocarcinoma (Fan et al, 2018).…”

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

“…Three LPIN isoforms have been described. LPIN1 is upregulated in lung adenocarcinoma tumor tissues, and high LPIN1 expression was correlated with poor prognosis of patients with lung adenocarcinoma (134). In breast cancer, previous results seem to indicate that the high LPIN expression is related to a good prognosis (135).…”