Novel agents for apoptosis of lung cancer

Institution:	The Burnham Institute for Medical Research
Investigator(s):	Xiao-Kun Zhang, Ph.D.
Award Cycle:	2002 (Cycle 11)	Grant #: 11RT-0081	Award: $787,977
Subject Area:	Cancer
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Tobacco consumption is the major risk factor for developing lung cancer, the leading cause of cancer death in California. Surgery, radiotherapy, and chemotherapy appear to have attained their maximum effects on improving morbidity, mortality, and quality of life in lung cancer patients. Although vitamin A and its natural and synthetic derivatives (retinoids) are effective agents in preventing lung cancer in animals, clinical trials using classical retinoids in cigarette smokers were not effective. The lack of efficacy of these conventional vitamin A derivatives is in part due to the induction of a protein called TR3 by nicotine. Thus, a new generation of retinoids is needed to overcome nicotine’s effect.

Recently, we found that the retinoid AHPN (also called CD437) could effectively destroy lung cancer cells via a process called apoptosis. Paradoxically, we found that AHPN and its nonretinoid derivatives also increased TR3 levels in lung cancer cells. However, we discovered that in response to AHPN TR3 migrates from the cell nucleus to an intracellular organelle called mitochondria to cause the death of lung cancer cells. In preliminary studies, we also found that TR3 binds to Bcl-2, a protein that is known to prevent cell death. Interestingly, the binding of TR3 to Bcl-2 is required for TR3 to reside on mitochondria and to cause cell death. These exciting observations offer new opportunities to develop novel therapies for tobacco-associated lung cancer.

We hypothesize that TR3 has opposing biological activities in lung cancer cells, depending on where it is located. TR3 induced by nicotine acts in the nucleus to promote lung cancer cell growth, while it migrates to mitochondria to cause lung cancer cell death when appropriate agents, such as the AHPN analog 3-Cl-AHPN, are present. We further hypothesize that binding of TR3 to Bcl-2 converts Bcl-2 from an inhibitor to a promoter of lung cancer cell death.

In this multidisciplinary project, we propose to develop (1) compounds that specifically induce migration of TR3 from the nucleus to mitochondria to cause lung cancer cell death and (2) small protein fragments called peptides that specifically and effectively bind to Bcl-2 to promote its killing activity. To accomplish our goals, we will study how AHPN causes TR3 to migrate in lung cancer cells and whether Bcl-2 is required for TR3 to reside on mitochondria to kill lung cancer cells. Based on the information obtained, we will design and synthesize new AHPN analogs and TR3-based Bcl-2-interacting peptides. The AHPN analogs and TR3-based peptides will be evaluated for their ability to kill lung cancer cells by inducing the migration of TR3 and by binding Bcl-2, respectively. The most potent analogs and peptides will be further evaluated for their anti-lung cancer activity in an animal model. Our proposed studies are novel and are highly relevant to the goals of TRDRP by addressing important issues regarding molecular controls on the effect of nicotine on lung tumor development. They will have significant impact on developing new agents for tobacco-associated lung cancer prevention and treatment.

Publications

Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in Lung Cancer Cells.
Periodical: Molecular and Cellular Biology			Index Medicus:
Authors: Kolluri S, Cao X, Bruey-Sedano N, Lin B, Lin F, Han Y-H, Dawson MI, Zhang XK				ART
Yr: 2003	Vol: 23	Nbr:	Abs:	Pg: 8651-8667

Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3
Periodical: Cell			Index Medicus:
Authors: Lin B, Kolluri S, Cao X, Li H, Han Y-H, Lin F, Reed JC, Zhang X-K				ART
Yr: 2004	Vol: 116	Nbr:	Abs:	Pg: 1-20

Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest.
Periodical: Journal of Medicinal Chemistry			Index Medicus:
Authors: Dawson MI, Harris D, Liu G, Hobbs P, Lange C, Jong L, Bruey-Sedano N, James S				ART
Yr: 2004	Vol: 47	Nbr:	Abs:	Pg: 3518 - 3536

Regulation of TR3-dependent apoptotic pathway by retinoids.
Periodical: FASEB Journal			Index Medicus:
Authors: Zhang X				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

Regulation of nur77 nuclear export by c-Jun N-terminal kinase and akt.
Periodical: Oncogene			Index Medicus:
Authors: Han YH, Cao X, Lin B, Lin F, Kolluri SK, Reed JC, Dawson MI, Zhang XK				ART
Yr: 2006	Vol:	Nbr:	Abs:	Pg: 1 - 13

Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in Lung Cancer Cells.
Periodical: Molecular and Cellular Biology			Index Medicus:
Authors: Kolluri S, Cao X, Bruey-Sedano N, Lin B, Lin F, Han Y-H, Dawson MI, Zhang XK				ART
Yr: 2003	Vol: 23	Nbr:	Abs:	Pg: 8651-8667

Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3
Periodical: Cell			Index Medicus:
Authors: Lin B, Kolluri S, Cao X, Li H, Han Y-H, Lin F, Reed JC, Zhang X-K				ART
Yr: 2004	Vol: 116	Nbr:	Abs:	Pg: 1-20

Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest.
Periodical: Journal of Medicinal Chemistry			Index Medicus:
Authors: Dawson MI, Harris D, Liu G, Hobbs P, Lange C, Jong L, Bruey-Sedano N, James S				ART
Yr: 2004	Vol: 47	Nbr:	Abs:	Pg: 3518 - 3536

Regulation of TR3-dependent apoptotic pathway by retinoids.
Periodical: FASEB Journal			Index Medicus:
Authors: Zhang X				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

Regulation of nur77 nuclear export by c-Jun N-terminal kinase and akt.
Periodical: Oncogene			Index Medicus:
Authors: Han YH, Cao X, Lin B, Lin F, Kolluri SK, Reed JC, Dawson MI, Zhang XK				ART
Yr: 2006	Vol:	Nbr:	Abs:	Pg: 1 - 13