Bcl-2 controls programmed cell death (apoptosis) pathway on mitochondria and the PI3K/AKT signaling pathway which regulates cell survival from the plasma membrane. Both pathways have been implicated in many cancers and other diseases. While some crosstalk between the two pathways is apparent, much remains to be understood with likely consequences for novel therapeutics for cancer and other diseases. Bcl-2 is characterized by a large, natively unstructured, regulatory loop that serves as a switch for activating its pro- or anti-apoptotic functions on mitochondria as we and others have reported. We recently discovered that the p85a regulatory subunit of phosphoinositide 3-kinase (PI3K) also interacts with the Bcl-2 loop. Our preliminary results demonstrate that the interaction enhances activation of PI3K and its downstream kinase AKT (protein kinase B) in vitro and in vivo and that the activation of PI3K/AKT signaling by Bcl-2 can be dissociated from its anti-apoptotic function. In several cancer cells lines, Bcl-2 expression enhances both basal and growth factor-induced AKT activation. We also found that short peptides derived from the loop of Bcl-2 inhibit Bcl-2/p85a interaction, AKT activation, and cell growth. The central hypothesis we will test is that Bcl-2 interaction with p85a can activate PI3K/AKT signaling by forming an active Bcl-2-containing PI3K signalosome. Our objectives are to use integrated multidisciplinary approaches to address several issues regarding the Bcl-2/p85 interaction: 1). Does Bcl-2 interaction with p85a contribute to elevated PI3K/AKT signaling in cancer cells in vitro and in vivo? 2). How does p85a interact with Bcl-2 and how is the interaction regulated? 3). Can we identify Bcl-2 peptide-based peptidomimetic inhibitors of Bcl-2-mediated PI3K/AKT activation for studying this new Bcl-2-mediated survival pathway? Our proposed studies will unravel a new Bcl-2-mediated PI3K/AKT signal pathway in cancer cells, which likely plays a critical role in enhancing the survival of cancer cells and the development of their resistance to chemo and radiation therapies. Our studies may also result in the identification of leads for developing novel Bcl-2-based PI3K inhibitors for treating human cancer and other lesions where Bcl-2 is often overexpressed.

Public Health Relevance

We propose to study the role of Bcl-2 interaction with p85a in mediating the activation of PI3K/AKT in cancer cells and the underlying molecular mechanisms. Our proposed studies are anticipated to identify an important new survival signaling pathway in cancer cells, which may serve as a new drug target.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Xu, Lin; Zeng, Zhiping; Zhang, Weidong et al. (2017) RXR? ligand Z-10 induces PML-RAR? cleavage and APL cell apoptosis through disrupting PML-RAR?/RXR? complex in a cAMP-independent manner. Oncotarget 8:12311-12322
Xie, Lei; Jiang, Fuquan; Zhang, Xindao et al. (2016) Honokiol sensitizes breast cancer cells to TNF-? induction of apoptosis by inhibiting Nur77 expression. Br J Pharmacol 173:344-56
Zeng, Zhiping; Sun, Zhe; Huang, Mingfeng et al. (2015) Nitrostyrene Derivatives Act as RXR? Ligands to Inhibit TNF? Activation of NF-?B. Cancer Res 75:2049-60
Zhang, Xiao-kun; Su, Ying; Chen, Liqun et al. (2015) Regulation of the nongenomic actions of retinoid X receptor-? by targeting the coregulator-binding sites. Acta Pharmacol Sin 36:102-12
Chen, Liqun; Wang, Zhi-Gang; Aleshin, Alexander E et al. (2014) Sulindac-derived RXR? modulators inhibit cancer cell growth by binding to a novel site. Chem Biol 21:596-607
Zhou, Yuqi; Zhao, Wei; Xie, Guobin et al. (2014) Induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38 MAPK. Carcinogenesis 35:2660-9
Wang, Guang-Hui; Jiang, Fu-Quan; Duan, Ying-Hui et al. (2013) Targeting truncated retinoid X receptor-? by CF31 induces TNF-?-dependent apoptosis. Cancer Res 73:307-18
Gao, Weiwei; Liu, Jie; Hu, Mengjie et al. (2013) Regulation of proteolytic cleavage of retinoid X receptor-? by GSK-3?. Carcinogenesis 34:1208-15
Wang, Zhi-Gang; Chen, Liqun; Chen, Jiebo et al. (2013) Synthesis and SAR study of modulators inhibiting tRXR?-dependent AKT activation. Eur J Med Chem 62:632-48
Wang, Guanghui; Guo, Xiaoyu; Chen, Haifeng et al. (2012) A resveratrol analog, phoyunbene B, induces G2/M cell cycle arrest and apoptosis in HepG2 liver cancer cells. Bioorg Med Chem Lett 22:2114-8

Showing the most recent 10 out of 13 publications