Abstract P2-06-24: Cannabinoid receptors agonist induces lysosome-mediated cell death in TNBC

Abstract

Abstract Breast cancer is one of the leading causes of death among women in the United States. Among all the breast cancer subtypes, triple-negative breast cancer (TNBC) is denoted as having the highest rate of mortality due to inefficacious therapy, drug resistance, and high recurrences rate. Despite many therapeutic advances over the past decades, novel therapeutic approaches are required to treat TNBC. Although lysosomes have recently been identified as novel targets in a variety of cancers, not much known about their role in breast cancer especially in TNBC. Due to the altered features of lysosomes in cancerous cells, its functional ability affects cell proliferation, metabolism, adaptation, and autophagy in tumor cells. Thus, the induction of lysosomal membrane permeabilization (LMP) may be used as a novel approach in controlling the aberrant cellular functions in TNBC. Cannabinoid receptor 2 (CB2) is expressed in breast cancer and its agonist JWH-015 has been shown to inhibit TNBC growth and metastasis. However, not much is known about the mechanisms by which JWH015 inhibit growth and metastasis. To investigate JWH015-mediated therapeutic mechanisms, we examined the lysosome-mediated cell death in TNBC cells. We found that JWH015 induces cell death in TNBC cells through lysosomal disruption mechanism. We also showed that JWH-015 treatment increases releases of lysosomal proteins, cathepsin D/B, and autophagy marker LC3B and that leads to activation of apoptotic cell death signaling in TNBC. These alterations result in the formation of autolysosomes to promote LMP. Our findings elucidate the mechanism by which JWH-015 promotes LMP induced autophagy and regulates TNBC cell proliferation. These studies elucidate novel lysosomal-mediated cell death mechanisms through activation of CB2 receptors in TNBC. Citation Format: Chatterjee N, Das S, Ahiwar D, Mishra S, Kaul K, Ganju R. Cannabinoid receptors agonist induces lysosome-mediated cell death in TNBC [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-24.