Prodigiosin Inhibition of autophagy is a promising strategy to augment the cytotoxicity of chemotherapeutic agents

 Cancer Letters 481 (2020) 15–23 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Prodigiosin impairs autophagosome-lysosome fusion that sensitizes T colorectal cancer to 5-fluorouracil-induced cell death a,b,1 a,b,1 a,b a,b a,b a,b Chong Zhao , ShaoZhuang Qiu , Jie He , Yao Peng , Haoming Xu , Zhiqiang Feng , a,b a,b a,b a,b,∗ Hongli Huang , Yanlei Du , Yongjian Zhou , Yuqiang Nie a Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People\'s Hospital, Guangzhou Medical University, Guangzhou, 510180, China b Department of Gastroenterology, Guangzhou First People\'s Hospital, School of Medical, South China University of Technology, Guangzhou, 510180, China ARTICLE INFO ABSTRACT Keywords: Chemotherapy failure is a major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. Prodigiosin Inhibition of autophagy is a promising strategy to augment the cytotoxicity of chemotherapeutic agents. 

 

We Colorectal cancer identifiedprodigiosin,asecondarymetaboliteproducedbyvariousbacteria,asanovelautophagyinhibitorthat Autophagyflux interfered with the autophagic flux in CRC cells by blocking autophagosome-lysosome fusion and lysosomal Chemotherapy cathepsin maturation, resulting in the accumulation of LC3B-II and SQSTM. Suppression of autophagy by pro- Apoptosis digiosin sensitized the CRC cells to 5-fluorouracil (5-Fu) in vitro, and the combination treatment markedly re- duced cancer cell viability partly via caspase-dependent apoptosis. Furthermore, prodigiosin and 5-Fu sy- nergistically inhibited CRC xenograft growth in vivo without any adverse effects. In conclusion, prodigiosin inhibits late stage autophagy and sensitizes tumor cells to 5-Fu, indicating its therapeutic potential in CRC. 1. Introduction and chemotherapy [10–12]. Autophagy is considered a pro-survival response by cancer cells against chemotherapeutic drugs, and its Colorectal cancer (CRC) is the third most prevalent cancer and the blockadecansensitize cancercellstochemotherapeuticagents. Several second leading cause of cancer-related deaths worldwide [1,2]. Al- ongoing clinical trials are analyzing the anti-cancer efficacy of autop- though surgical resection is the primary therapeutic approach for CRC, hagy inhibitors either as single agents or in combination with other it is precluded for most advanced stage patients 3x FLAG price. At present, 5-fluor- drugs [13–15]. In addition, several autophagy inhibitors have be###http://www.glpbio.com/simage/GA11233-L-NAME-hydrochloride-1.png####en ouracil (5-Fu)-based chemotherapy is the mainstream adjuvant treat- identified that are derived from natural compounds. ment available for advanced stage CRC [3,4]. However, despite im- Prodigiosin,aredpigmentwithapyrrolylpyrrometheneskeleton,is provements in survival rates, prolonged 5-Fu usage frequently leads to producedby Serratia marcescensandotherbacterialspecies(Fig Trizma maleate.1A).It tumorrecurrenceanddrugresistance,whicheventuallydecreaseslong- is a bioactive secondary metabolite with antibacterial, antifungal, an- termsurvival[5].Therefore,itisessentialtoidentifynoveltherapeutic timalarial, immunosuppressive and anticancer properties [16]. Prodi- targets in CRC cells, in order to improve treatment efficacy and out- giosin and its analog obatoclaxare have been tested in several clinical comes. For instance, combination therapies that simultaneously target trials as anti-cancer agents with or without other chemotherapeutic cancer specific pathways and sensitize the to chemotherapeutic drugs [17]. 

 

A recent study showed that prodigiosin can induce p53 agents are highly promising against CRC [6]. target genes and inhibit the Wnt/β-catenin signaling [18,19]. It also Autophagyisanevolutionarilyconservedself-digestionprocessthat exerts an anticancer effect by modulating mTOR-dependent autophagy degrades/recycles damaged organelles and proteins in order to sustain in melanoma cells [20]. Furthermore, prodigiosin can also trigger en- cellularmetabolism[7 P 22077,8].Itisdriventhroughthecoordinatedactionof doplasmic reticulum stress and induce autophagic cell death in glio- several autophagy-related proteins, and depends on the formation of blastoma cells [21]. However, its exact molecular targets and the me- autophagosomes, followed by their fusion with lysosomes to form au- chanisms through which prodigiosin regulates autophagy in CRC cells tolysosomes[9].Anincreasingnumberofstudieshavebeenfocusingon remain unclear. the relationship between autophagy and tumorigenesis, progression In this study, we found that prodigiosin not only inhibited the ∗ Corresponding author. Guangzhou First People\'s Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, 510180, China. E-mail address: eynieyuqiang@scut.edu.cn (Y. Nie). 1 These authors have contributed equally to this work. https://doi.org/10.1016/j.canlet.2020.03.010 Received 11 July 2019; Received in revised form 8 March 2020; Accepted 10 March 2020 0304-3835/ © 2020 Elsevier B.V. All rights reserved.