Aryl hydrocarbon receptor sulfenylation promotes glycogenolysis and rescues cancer chemoresistance
Nannan Zhou, Jie Chen, Zheng Ling, Chaoqi Zhang, Yabo Zhou, Dianheng Wang, Li Zhou, Zhenfeng Wang, Nan Sun, Xin Wang, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Bo Huang
Nannan Zhou, Jie Chen, Zheng Ling, Chaoqi Zhang, Yabo Zhou, Dianheng Wang, Li Zhou, Zhenfeng Wang, Nan Sun, Xin Wang, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Bo Huang
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Research Article Cell biology Metabolism

Aryl hydrocarbon receptor sulfenylation promotes glycogenolysis and rescues cancer chemoresistance

Abstract

Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells’ response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.

Authors

Nannan Zhou, Jie Chen, Zheng Ling, Chaoqi Zhang, Yabo Zhou, Dianheng Wang, Li Zhou, Zhenfeng Wang, Nan Sun, Xin Wang, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Bo Huang

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Figure 2

Glycogenolysis drives PPP in DRCs in response to drug molecules.

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Glycogenolysis drives PPP in DRCs in response to drug molecules. (A) Ove...
(A) Overview of 3 glucose metabolic pathways: glycolysis, glycogen metabolism, and PPP are shown. (B) MCF-7/DDP or A549/5-Fu cells cultured in 13C-glucose were switched to 12C-glucose at the time of treatment with DDP or 5-Fu for 1 or 3 hours, and 13C-labeled R5P was detected by LC-MS/MS. (C) MCF-7/DDP or A549/5-Fu cells cultured in 13C-glucose were pretreated with GPI (50 μM) for 2 hours and switched to 12C-glucose at the time of chemo treatment. 13C-labeled R5P was detected by LC-MS/MS. (D and E) MCF-7/DDP or A549/5-Fu cells were treated with GPI for 2 hours prior to treatment with DDP or 5-Fu for 24 hours. NADPH/NADP+ (D) and ROS levels (E) were analyzed. (F) The expression of PYGL in MCF-7/DDP or A549/5-Fu cells transduced with si-NC or si-PYGL was analyzed by Western blot. (G) MCF-7/DDP or A549/5-Fu cells cultured in 13C-glucose transduced with si-NC or si-PYGL were switched to 12C-glucose for 4 hours of drug treatment, and 13C-labeled R5P or S7P was detected by LC-MS/MS. (H and I) MCF-7/DDP or A549/5-Fu cells transduced with si-NC or si-PYGL were treated with DDP or 5-Fu for 24 hours. NADPH/NADP+ (H) and ROS levels (I) were analyzed. (J) MCF-7/DDP and A549/5-Fu transduced with si-NC or si-PYGL were treated with DDP or 5-Fu for 48 hours. The cell viability was analyzed. (K) MCF-7/DDP or A549/5-Fu cells cultured in 12C-glucose pretreated with GPI for 2 hours were switched to 13C-glucose for 4 hours of drug treatment, and 13C-labeled R5P was detected by LC-MS/MS. All experiments were repeated 3 times. n = 3. All error bars are mean ± SD. P values were calculated by 2-tailed unpaired Student’s t test (B) or 1-way ANOVA followed by Bonferroni’s test (C–E and G–J). *P < 0.05, **P < 0.01, ***P < 0.001. G6pd, glucose-6-phosphate dehydrogenase; m+, number of carbon atoms labeled with 13C.