Identification of Gossypol Acetate as an Autophagy Modulator with Potent Anti-tumor Effect against Cancer Cells

Cai, Bicheng1,2,3; Gong, Liang2; Zhu, Yiying2; Kong, Lingmei2; Ju, Xiaoman2; Li, Xue2; Yang, Xiaodong1; Zhou, Hongyu2,4,5; Li, Yan1,2

2022-03-02

10.1021/acs.jafc.1c06399

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY   影响因子和分区

0021-8561

1520-5118

Autophagy, an evolutionarily conserved process, is intricately involved in many aspects of human health and a variety of human diseases, including cancer. Discovery of small-molecule autophagy modulators with potent anticancer effect would be of great significance. To this end, a natural product library consisting of 170 natural compounds were screened as autophagy modulators with potent cytotoxicity in our present study. Among these compounds, gossypol acetate (GAA), the mostly used medicinal form of gossypol, was identified. GAA effectively increased the number of autophagic puncta in GFP-LC3B-labeled 293T cells and significantly decreased cell viability in different cancer cells. In A549 cells, GAA at concentrations below 10 /AM triggered caspase-independent cell death via targeting autophagy, as evidenced by elevated LC3 conversion and decreased p62/SQSTM1 levels. Knocking down of LC3 significantly attenuated GAA-induced cell death. Mechanistically, GAA at low concentrations induced autophagy through targeting AMPK-mTORC1-ULK1 signaling. Interestingly, high concentrations of GAA induced LC3 conversion, p62 accumulation, and yellow autophagosome formation, indicating that GAA at high concentrations blocked autophagic flux. Mechanistically, GAA decreased intracellular ATP level and suppressed lysosome activity. Exogenous ATP partially reversed the inhibitory effect of GAA on autophagy, suggesting that decreased ATP level and lysosome activity might be involved in the blocking of autophagy flux by GAA. Collectively, our present study reveals the mechanisms by which GAA modulates autophagy and illustrates whether autophagy regulation by GAA is functionally involved in GAA-induced cancer cell death.

autophagy gossypol acetate apoptosis adenosine 5 '-monophosphate (AMP)-activated protein kinase (AMPK) unc-51-like autophagy-activating kinase 1 (ULK1) mammalian target of rapamycin complex-1 (mTORC1) ATP lysosome cancer cell death

SCI ; EI

英语

其他

National Natural Science Foundation of China[82160697,81773783] ; Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Research Fundamental Research Project[202101AY070001001] ; Yunnan Fundamental Research Projects["202101AT070155","2018FB147"]

Agriculture ; Chemistry ; Food Science & Technology

Agriculture, Multidisciplinary ; Chemistry, Applied ; Food Science & Technology

WOS:000773642500015

AMER CHEMICAL SOC

AGRICULTURAL SCIENCES

Web of Science

1.Yunnan Univ, Key Lab Med Chem Nat Resource, Minist Educ, Kunming 650091, Yunnan, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
3.Southern Univ Sci & Technol, Inst Shenzhen Resp Dis, Affiliated Hosp 1, Shenzhen Peoples Hosp, Shenzhen 518020, Peoples R China
4.Kunming Med Univ, Sch Pharmaceut Sci, Kunming 650500, Yunnan, Peoples R China
5.Kunming Med Univ, Yunnan Key Lab Pharmacol Nat Prod, Kunming 650500, Yunnan, Peoples R China

Cai, Bicheng,Gong, Liang,Zhu, Yiying,et al. Identification of Gossypol Acetate as an Autophagy Modulator with Potent Anti-tumor Effect against Cancer Cells[J]. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY,2022,70(8).

Cai, Bicheng.,Gong, Liang.,Zhu, Yiying.,Kong, Lingmei.,Ju, Xiaoman.,...&Li, Yan.(2022).Identification of Gossypol Acetate as an Autophagy Modulator with Potent Anti-tumor Effect against Cancer Cells.JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY,70(8).

Cai, Bicheng,et al."Identification of Gossypol Acetate as an Autophagy Modulator with Potent Anti-tumor Effect against Cancer Cells".JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 70.8(2022).