Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis

Burikhanov, R., Hebbar, N., Noothi, S.K., Shukla, N., Sledziona, J., Araujo, N., Kudrimoti, M., Wang, Q.J., Watt, D.S., Welch, D.R., Maranchie, J., Harada, A. & Rangnekar, V.M.

Cell reports 18, 508-519 (2017)

Speaker: Jia-Wen Chen (陳佳文)                                   Time: 15:10~16:00, Nov. 08, 2017

Commentator: Dr. Li-Wha Wu (吳梨華老師)              Place: Room 601

Abstract:

Prostate apoptosis response-4 (Par-4) is a pro-apoptotic tumor suppressor protein, which is selectively secreted to induce apoptosis of diverse cancer cells but not normal cells.¹ The authors previously reported that elevation of extracellular Par-4 in the conditioned medium (CM) induces apoptosis of the cancer cells.² Furthermore, systemic elevation of Par-4 in the mice inhibited tumor growth.² In this paper, the authors screened a panel of FDA (Food and Drug Administration)-approved drugs for Par-4 secretion inducers. They identified the anti-malarial drug chloroquine (CQ) and its hydroxylated analog, HCQ, as the inducers of Par-4 secretion from the normal cells. The authors further confirmed that CQ is a robust inducer of Par-4 secretion in the normal cells of mice, prostate cancer cells and lung cancer cells of the clinical cancer patients. The authors reveal that CQ induced tumor cell apoptosis and inhibited lung tumor nodules via Par-4 secretion from normal cells in a paracrine manner. The authors have reported that p53 function is essential for classical Par-4 secretion. Here, they further disclose that p53 activated by CQ is required for induction of Par-4 secretion. Mechanistically, p53 induces Rab8b (a GTPase essential for vesicle transport of Par-4) to the plasma membrane prior to secretion. Furthermore, p53 induced by CQ directly bind to the promoter of Rab8b and promotes Par-4 secretion through upregulation of Rab8b. In conclusion, CQ induces p53- and Rab8b-dependent Par-4 secretion from normal cells, which inhibits metastatic tumor growth. CQ also shows encouraging results in clinical trials designed to test the potential repurposing of CQ for cancer treatment.

References:

1          Hebbar, N., Wang, C. & Rangnekar, V. M. Mechanisms of apoptosis by the tumor suppressor Par‐4. J. Cell. Physiol. 227, 3715-3721 (2012).

2          Burikhanov R., Sviripa V.M., Hebbar N., Zhang W., Layton W.J., Hamza A., Zhan C.G., Watt D.S., Liu C. & Rangnekar Rangnekar V.M. Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat. Chem. Biol. 10, 924-926, doi:10.1038/nchembio.1631 (2014).