2. Academic Validation
  3. Cytochalasin Q exerts anti-melanoma effect by inhibiting creatine kinase B

Cytochalasin Q exerts anti-melanoma effect by inhibiting creatine kinase B

  • Toxicol Appl Pharmacol. 2022 Apr 15:441:115971. doi: 10.1016/j.taap.2022.115971.
Yi Lu 1,  Peng Zhang 2,  Hongdan Chen 3,  Qingyi Tong 1,  Jia Wang 2,  Qing Li 1,  Cheng Tian 1,  Jian Yang 1,  Senlin Li 1,  Zijun Zhang 2,  Huimin Yuan 1,  Ming Xiang 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Breast and Thyroid Surgical Department, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400014, China.
  • 4 Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
PMID: 35276125 DOI: 10.1016/j.taap.2022.115971
Abstract

Due to the pivotal role of microfilament in Cancer cells, targeting microfilaments with cytochalasins is considered a promising Anticancer strategy. Here, we obtained cytochalasin Q (CQ) from Xylaria sp. DO1801, the endophytic fungi from the root of plant Damnacanthus officinarum, and discovered its anti-melanoma activity in vivo and in vitro attributing to microfilament depolymerization. Mechanistically, CQ directly bound to and inactivated Creatine Kinase B (CKB), an enzyme phosphorylating creatine to phosphocreatine (PCr) and regenerating ATP to cope with high energy demand, and then inhibited the creatine metabolism as well as cytosolic glycolysis in melanoma cells. Preloading PCr recovered ATP generation, reversed microfilament depolymerization and blunted anti-melanoma efficacy of CQ. Knockdown of CKB resulted in reduced ATP level, perturbed microfilament, inhibited proliferation and induced Apoptosis, and manifested lower sensitivity to CQ. Further, we found that either CQ or CKB depletion suppressed the PI3K/Akt/FOXO1 pathway, whereas 740Y-P, a PI3K agonist, elevated protein expression of CKB suppressed by CQ. Taken together, our study highlights the significant anti-melanoma effect and proposes a PI3K/Akt/FOXO1/ CKB feedback circuit for the activity of CQ, opening new opportunities for current chemotherapy.

Keywords

Creatine kinase B; Creatine metabolism; Cytochalasin Q; Melanoma; Microfilament.

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