# Beyond apoptosis, Bcl-xL in tumor metastasis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $390,659

## Abstract

This proposed study is to advance our understanding of the molecular mechanism of nuclear Bcl-xL in
tumor metastasis. B cell lymphoma 2 (Bcl-2) family proteins are known to play an important role in the control
of apoptosis and the dysregulation in cancer. Bcl-xL is one of the anti-apoptotic members of the Bcl-2 family,
frequently overexpressed in various cancer cells. It controls cellular commitment to apoptosis at the
mitochondria and prevents cell death. Abrogating the anti-apoptotic activity of Bcl-xL as well as other anti-
apoptotic Bcl-2 members as a putative target of cancer therapy has received significant research attention.
 Using an avian virus RCASBP-based in vivo mouse model for pancreatic neuroendocrine tumors
(panNETs), we found that overexpression of Bcl-xL stimulates metastasis of primary panNETs without blocking
apoptosis. We showed that ABT-737, a small molecular inhibitor of Bcl-xL, does not impair Bcl-xL-induced cell
migration. We demonstrated that Bcl-xL promotes metastasis independent of its anti-apoptotic activity and its
residence at the mitochondria in panNET cell lines as well as breast cancer cell line. We showed that nuclear-
targeted Bcl-xL, not mitochondrial Bcl-xL nor Bcl-xL outside the nucleus, promotes EMT and tumor cell
migration. Furthermore, Bcl-xL increases H3K4me3 on the promoter of TGFβ1 to upregulate the expression,
and TGFβ neutralizing antibodies block the metastatic function of Bcl-xL in vitro. Based on our data, we
hypothesize that the metastatic function of Bcl-xL is attributed primarily to its nuclear function.
 To test this hypothesis, we will use multiple experimental systems, which include Bcl-xL mutants, Bcl-xL
knockout, doxycycline-inducible overexpression and shRNA, cancer cell lines, and mouse models for human
cancer. The findings from cancer cells and mouse models will be cross-examined and the tests reciprocated.
Information derived from this proposed study is expected to be useful in establishing the mechanisms by which
Bcl-xL promotes metastasis, while providing significant insights into further development of drugs
therapeutically targeting Bcl-xL in the treatment of metastatic cancers.

## Key facts

- **NIH application ID:** 9830622
- **Project number:** 5R01CA204916-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Yi-Chieh Nancy Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,659
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830622

## Citation

> US National Institutes of Health, RePORTER application 9830622, Beyond apoptosis, Bcl-xL in tumor metastasis (5R01CA204916-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9830622. Licensed CC0.

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