Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis

Ying Tao; Zijun Gong; Sheng Shen; Yaqi Ding; Rui Zan; Bohao Zheng; Wentao Sun; Chaolin Ma; Mengxuan Shu; Xiao Lu; Han Liu; Xiaoling Ni; Houbao Liu; Tao Suo

doi:10.1016/j.isci.2024.109659

Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis

iScience. 2024 Apr 8;27(5):109659. doi: 10.1016/j.isci.2024.109659. eCollection 2024 May 17.

Authors

Ying Tao¹, Zijun Gong^{2

3

4

5}, Sheng Shen^{2

3

4

5}, Yaqi Ding⁶, Rui Zan^{2

3

4

5}, Bohao Zheng^{2

3

4

5}, Wentao Sun^{2

3

4

5}, Chaolin Ma^{2

3

4

5}, Mengxuan Shu^{2

3

4

5}, Xiao Lu^{2

3

4

5}, Han Liu^{2

3

4

5}, Xiaoling Ni^{2

3

4

5}, Houbao Liu^{1

2

3

4

5}, Tao Suo^{2

3

4

5}

Affiliations

¹ Department of General Surgery, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
² Department of Biliary Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Shanghai Engineering Research Center of Biliary Tract Minimal Invasive Surgery and Materials, Shanghai, China.
⁴ Biliary Tract Disease Institute, Fudan University, Shanghai, China.
⁵ The Center of Biliary Disease Center, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Ruijin Hospital LuWan Branch, Shanghai Jiao Tong University School of Medicine Central Laboratory, Shanghai, China.

Abstract

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies 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 RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

Keywords: Cancer; Cell biology; Molecular biology.