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 1

Drug-resistant tumor cells use higher ROS to produce NADPH during treatment.

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Drug-resistant tumor cells use higher ROS to produce NADPH during treatm...
(A and B) Different drug-resistant tumor cell lines including MCF-7/DDP, MCF-7/ADR, A549/DDP, A549/5-Fu, HCT116/Oxa, SW1990/Gem, B16/TAX, and 4T-1/DDP and their parental tumor cells were treated with their corresponding chemo drugs for 24 hours. ROS levels (A) and the ratio of NADPH/NADP+ (B) were analyzed. (C and D) MCF-7/DDP and A549/5-Fu, respectively, were treated with DDP (20 μM) or 5-Fu (100 μM) alone or in combination with 6-AN (50 μM) for 24 hours. NADPH/NADP+ (C) and ROS levels (D) were analyzed. (E) The expression of G6PD in MCF-7/DDP and A549/5-Fu cells transduced with si-NC or si-G6PD was analyzed by Western blot. (F and G) MCF-7/DDP and A549/5-Fu cells transduced with si-NC or si-G6PD were treated with DDP or 5-Fu for 24 hours. NADPH/NADP+ (F) and ROS levels (G) were analyzed. (H) MCF-7 and MCF-7/DDP or A549 and A549/5-Fu were treated with DDP or 5-Fu for 12 hours, followed by the LC-MS/MS analysis of R5P, S7P, or E4P. (I and J) MCF-7/DDP or A549/5-Fu cells were pretreated with NAC (5 mM) for 12 hours prior to treatment with DDP or 5-Fu. NADPH/NADP+ (I) and ROS levels (J) were analyzed. All experiments were repeated 3 times. n = 3. All error bars are mean ± SD. P values were calculated by 1-way ANOVA followed by Bonferroni’s test (A–D, F, and G). *P < 0.05, **P < 0.01, ***P < 0.001. NC, negative control; LC-MS/MS, liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.