Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis
Ravshan Burikhanov, Nikhil Hebbar, Sunil K Noothi, Nidhi Shukla, James Sledziona, Nathália Araujo, Meghana Kudrimoti, Qing Jun Wang, David S Watt, Danny R Welch, Jodi Maranchie, Akihiro Harada, Vivek M Rangnekar, Ravshan Burikhanov, Nikhil Hebbar, Sunil K Noothi, Nidhi Shukla, James Sledziona, Nathália Araujo, Meghana Kudrimoti, Qing Jun Wang, David S Watt, Danny R Welch, Jodi Maranchie, Akihiro Harada, Vivek M Rangnekar
Abstract
The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings indicate that CQ induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumor growth.
Keywords: Par-4; Rab8b; apoptosis; chloroquine; metastasis-inhibition; p53; secretagogues.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Figures
References
- Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 2007;117:326–336.
- Boghaert ER, Sells SF, Walid AJ, Malone P, Williams NM, Weinstein MH, Strange R, Rangnekar VM. Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues. Cell Growth Differ. 1997;8:881–890.
- Boya P, Gonzalez-Polo RA, Poncet D, Andreau K, Vieira HL, Roumier T, Perfettini JL, Kroemer G. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003;22:3927–3936.
- Burikhanov R, Zhao Y, Goswami A, Qiu S, Schwarze SR, Rangnekar VM. The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell. 2009;138:377–388.
- Burikhanov R, Shrestha-Bhattarai T, Qiu S, Shukla N, Hebbar N, Lele SM, Horbinski C, Rangnekar VM. Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4. Cancer Res. 2013;73:1011–1019.
- Burikhanov R, Shrestha-Bhattarai T, Hebbar N, Qiu S, Zhao Y, Zambetti GP, Rangnekar VM. Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4. Cell Rep. 2014a;6:271–277.
- Burikhanov R, Sviripa VM, Hebbar N, Zhang W, Layton WJ, Hamza A, Zhan C-G, Watt DS, Liu C, Rangnekar VM. Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat. Chem. Biol. 2014b;10:924–926.
- Dupont N, Jiang S, Pilli M, Ornatowski W, Bhattacharya D, Deretic V. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1b. EMBO J. 2011;30:4701–4711.
- el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B. Definition of a consensus binding site for p53. Nat. Genet. 1992;1:45–49.
- García-Cao I, Duran A, Collado M, Carrascosa MJ, Martín-Caballero J, Flores JM, Diaz-Meco MT, Moscat J, Serrano M. Tumoursuppression activity of the proapoptotic regulator Par4. EMBO Rep. 2005;6:577–583.
- Grieve AG, Rabouille C. Golgi bypass: skirting around the heart of classical secretion. Cold Spring Harb. Perspect. Biol. 2011;3:a005298.
- Hebbar N, Wang C, Rangnekar VM. Mechanisms of apoptosis by the tumor suppressor Par-4. J. Cell. Physiol. 2012;227:3715–3721.
- Klausner RD, Donaldson JG, Lippincott-Schwartz J. Brefeldin A: insights into the control of membrane traffic and organelle structure. J. Cell Biol. 1992;116:1071–1080.
- Loehberg CR, Thompson T, Kastan MB, Maclean KH, Edwards DG, Kittrell FS, Medina D, Conneely OM, O’Malley BW. Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis. Cancer Res. 2007;67:12026–12033.
- Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J. Clin. Invest. 2008;118:79–88.
- Maes H, Kuchnio A, Peric A, Moens S, Nys K, De Bock K, Quaegebeur A, Schoors S, Georgiadou M, Wouters J, et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell. 2014;26:190–206.
- Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 2014;15:81–94.
- Maycotte P, Aryal S, Cummings CT, Thorburn J, Morgan MJ, Thorburn A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy. 2012;8:200–212.
- Rebecca VW, Amaravadi RK. Emerging strategies to effectively target autophagy in cancer. Oncogene. 2016;35:1–11.
- Rosenfeldt MT, O’Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013;504:296–300.
- Sato T, Iwano T, Kunii M, Matsuda S, Mizuguchi R, Jung Y, Hagiwara H, Yoshihara Y, Yuzaki M, Harada R, Harada A. Rab8a and Rab8b are essential for several apical transport pathways but insufficient for ciliogenesis. J. Cell Sci. 2014;127:422–431.
- Sobajima T, Yoshimura S, Iwano T, Kunii M, Watanabe M, Atik N, Mushiake S, Morii E, Koyama Y, Miyoshi E, Harada A. Rab11a is required for apical protein localisation in the intestine. Biol. Open. 2014;4:86–94.
- Sohn TA, Bansal R, Su GH, Murphy KM, Kern SE. High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter. Carcinogenesis. 2002;23:949–957.
- Stenmark H, Olkkonen VM. The Rab GTPase family. Genome Biol. 2001;2 REVIEWS3007.
- Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–848.
- Xia Y, Liu Y-L, Xie Y, Zhu W, Guerra F, Shen S, Yeddula N, Fischer W, Low W, Zhou X, et al. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci. Transl. Med. 2014;6:263ra161.
- Yu X, Harris SL, Levine AJ. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006;66:4795–4801.
- Zhao Y, Burikhanov R, Qiu S, Lele SM, Jennings CD, Bondada S, Spear B, Rangnekar VM. Cancer resistance in transgenic mice expressing the SAC module of Par-4. Cancer Res. 2007;67:9276–9285.
- Zhao Y, Burikhanov R, Brandon J, Qiu S, Shelton BJ, Spear B, Bondada S, Bryson S, Rangnekar VM. Systemic Par-4 inhibits non-autochthonous tumor growth. Cancer Biol. Ther. 2011;12:152–157.
Source: PubMed