Back to Search
Start Over
Fasting-induced RNF152 re-sensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis
- Publication Year :
- 2023
- Publisher :
- Research Square Platform LLC, 2023.
-
Abstract
- Accumulating evidence indicates that the lysosomal Ragulator complex is essential for the full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting is known to upregulate the ring finger protein 152 (RNF152) and mediate the metabolic status of cells. Here we report that RNF152 regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator, and attenuates gemcitabine resistance in gallbladder cancer (GBC). The effects of RNF152 expression on molecular behavior were analyzed. RNF152 and p18 levels were detected in tissues, and detailed mechanistic studies were undertaken by using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates the expression of RNF152. RNF152 overexpression increases the sensitivity of GBC cells to the chemotherapeutic drug gemcitabine, whereas silencing RNF152 exhibited the opposite effect. Our study verified that fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency induces the increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity in GBC. Our research suggests that RNF152 is a fasting sensor and an important regulator of the mTORC1 signal. RNF152 functions as a tumor suppressor that can suppress the activity of mTORC1 to inhibit glycolysis and enhance the sensitivity of gemcitabine in GBC. RNF152 may have potential in the therapeutic management of GBC.
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........ffabdb425854d4f7d01776ca79223dca