AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA

Abstract

Gastric cancer (GC) remains the third leading cause of cancer-related deaths. Chemoresistance is the major determinant of GC treatment failure. To explore the molecular mechanisms of GC chemoresistance, mass spectrometry was performed to detect the genes altered in expression between chemoresistant and chemosensitive GC. PRKA kinase anchor protein 8L (AKAP-8L) was identified as one of the top upregulated genes in chemoresistant GC tissues. Moreover, the higher AKAP-8L expression was associated with the lower survival rate in GC patients. Overexpression of AKAP-8L enhanced the GC cell stemness and chemoresistance of oxaliplatin in vivo and in vitro. AKAP-8L deficiency obtained the opposite results. Mechanistically, AKAP-8L interacted with Stearoyl-CoA desaturase 1 (SCD1) mRNA and IGF2BP1 protein, and regulated SCD1 mRNA stability via IGF2BP1-dependent manner. SCD1 played a critical role in mediating the function of AKAP-8L in GC cell stemness and chemoresistance. Clinically, AKAP-8L and SCD1 protein levels was positively associated with human GC chemoresistance. Taken together, our results demonstrated that AKAP-8L facilitates GC chemoresistance via regulating SCD1-mediated stemness of GC cells. AKAP8L may represent a novel therapeutic target to overcome GC chemoresistance.

Integrative analysis identifies AKAP8L as an immunological and prognostic biomarker of pan-cancer

“…As demonstrated by studies, AKAP8L stimulates cell proliferation / migration in various cancers, such a sd colon cancer, gastric cancer and esophageal squamous cell carcinoma, and can interact with mTORC1 and promote cell growth. Thus, it may be a prospective target for the treatment of cancers [ 9 , 15 , 16 , 25 ].…”

“…It has been previously proved that the high AKAP8L expression is associated with poor prognosis in esophageal squamous cell carcinoma, serving as an independent prognostic factor for the disease [ 9 ]. Zhang et al found that AKAP8L can enhance the dryness and chemoresistance of gastric cancer cells by stabilizing the expression of SCD1 mRNA [ 15 ]. A previous study proved that AKAP8L can promote cell growth by interacting with mTORC1 [ 16 ].…”

Regulatory mechanisms and therapeutic implications of insulin-like growth factor 2 mRNA-binding proteins, the emerging crucial m6A regulators of tumors

“…IGF2BPs not only promote cancer progression but also blunt the sensitivity to anti-tumor therapies. In a nutshell, IGF2BPs expedite the development of drug resistance by enhancing tumor stemness 5 , 116 , blocking apoptosis 19 , inducing metabolic reprogramming 16 , 64 , 70 , etc. Logically, it follows that targeting IGF2BPs may be a novel anti-tumor strategy.…”

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

“…Luo et al showed that SCD1 expression supported radiation resistance in esophageal squamous cell carcinoma [ 164 ]. Zhang et al showed that SCD1 was essential to stem cell-like behavior and chemoresistance in gastric carcinoma [ 165 ]. Morais et al [ 166 ] and Parik et al [ 167 ] showed that glioblastoma aggressiveness and temozolomide resistance depended on SCD1 expression.…”