ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma

Abstract

Currently, only a few available targeted drugs are considered to be effective in stomach adenocarcinoma (STAD) treatment. The PARP inhibitor olaparib is a molecularly targeted drug that continues to be investigated in BRCA-mutated tumors. However, in tumors without BRCA gene mutations, particularly in STAD, the effect and molecular mechanism of olaparib are unclear, which largely restricts the use of olaparib in STAD treatment. In this study, the in vitro results showed that olaparib specifically inhibited cell growth and migration, exerting antitumor effect in STAD cell lines. In addition, a ClC-3/SGK1 regulatory axis was identified and validated in STAD cells. We then found that the down-regulation of ClC-3/SGK1 axis attenuated olaparib-induced cell growth and migration inhibition. On the contrary, the up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced cell growth and migration inhibition, and the enhancement effect could be attenuated by SGK1 knockdown. Consistently, the whole-cell recorded chloride current activated by olaparib presented the same variation trend. Next, the clinical data showed that ClC-3 and SGK1 were highly expressed in human STAD tissues and positively correlated (r = 0.276, P = 0.009). Furthermore, high protein expression of both ClC-3 (P = 0.030) and SGK1 (P = 0.006) was associated with poor survival rate in STAD patients, and positive correlations between ClC-3/SGK1 and their downstream molecules in STAD tissues were demonstrated via the GEPIA datasets. Finally, our results suggested that olaparib inhibited the PI3K/AKT pathway in STAD cells, and up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced PI3K/AKT pathway inhibition. The animal experiments indicated that olaparib also exerted antitumor effect in vivo. Altogether, our findings illustrate that olaparib exerts antitumor effect in human STAD, and ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect. Up-regulation of the ClC-3/SGK1 axis may provide promising therapeutic potential for the clinical application of olaparib in STAD treatment.

Identification and Construction of a Long Noncoding RNA Prognostic Risk Model for Stomach Adenocarcinoma Patients

“…Stomach adenocarcinoma (STAD), as the most common type of gastric cancer (GC), is characterized by rapid growth and strong invasiveness [ 1 ]. It is among one of the leading causes of cancer-related death worldwide [ 2 , 3 ].…”

Early loss of endogenous NAD+ following rotenone treatment leads to Sarm1 activation that is ameliorated by PARP inhibition

“…To further understand the physiological relevance of PARP inhibition by Olaparib in rotenone induced pathological conditions, we extended our data in the fruitfly Drosophila melanogaster . Olaparib has shown promise as an anti-cancer chemotherapeutic drug and is sold under the trade name Lynparza to treat ovarian cancer 33[50, 51]. Due to its known prospect in drug repurposing, we selected Olaparib for PARP inhibition instead of PJ34 in our fly studies.…”

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

“…35 Moreover, ClC-3 may be a critical subunit or cooperative protein for the assembly of functional proteins or membrane receptors, such as NADPH oxidase 1 (NOX1), 36 protein kinase C (PKC), 37 calcium/calmodulin-dependent protein kinase II (CamKII), 21 matrix metalloproteinase-2 (MMP-2) receptors, 38 Sirtuin 1 (Sirt1), 39 SRY-box transcription factor 2 (SOX2), 40 and serumand glucocorticoid-regulated kinase 1 (SGK1). 41 Notably, angiotensin II (AngII), lipopolysaccharide (LPS), interleukin (IL), endothelin 1 (ET1), transforming growth factor-b1 (TGF-b1), and tumor necrosis factor-a (TNF-a) can promote the ClC-3 expression and stimulate the activation of multiple inflammatory signaling pathways such as nuclear factor kappa B (NF-kB), 36,42 Janus kinase (JAK)-signal transducer and activator of transcription (STAT), 43 and LPS/ Toll-like receptor 4 (TLR4). 44 ClC-3 knockout or inhibition was found to suppress these inflammatory signaling pathways, alleviating the induction of inflammation both in vitro and in vivo.…”