Devasis Chatterjee, PHD
Assistant Professor of Medicine (Research)
Work: +1 401-444-9039
Resistance to chemotherapy and metastatic tumor growth are major factors thatdirectly lead to the demise of cancer patients. My laboratory studies the regulation of 2 proteins that directly affect tumor cell death (RKIP) and survival (STAT3). We have found that RKIP is a negative regulator of STAT3. We are validating if RKIP is a candidate to be utilized as the basis for molecular-targeted therapeutic strategy for cancer.
Research DescriptionTargeting a specific gene or gene product is becoming a prominent feature of molecular cancer therapy where the ultimate therapeutic goal is to trigger tumor-selective apoptosis or growth arrest. We discovered that Raf kinase inhibitory protein (RKIP) expression was robustly induced when human cancer cells were exposed to clinically relevant anticancer agents and induced to undergo apoptosis. The direct correlation between RKIP expression and the extent of apoptosis suggests that up-regulation of RKIP is one of the mechanisms that sensitizes cancer cells to apoptotic signals in response to chemotherapeutic agent-induced DNA damage. RKIP disrupts the Raf-1MEK1/2ERK1/2 and NF-B signaling pathways thereby abrogating the survival and anti-apoptotic properties of these signaling pathways. Thus, regulation of cell survival pathways by RKIP suggests that this protein may play a pivotal role in tumor progression. In addition to the Raf and NF-B pathways, our recent findings indicate that RKIP interferes with the Src/Jak (Janus kinases) and STAT (signal transducer and activators of transcription) cell survival signaling pathway. Thus, RKIP behaves as a multiple kinase inhibitor. Studies, including our own, have demonstrated that RKIP expression is predictive of clinical outcome and is a metastasis suppressor in many human tumors. Significantly, in gastric cancer there is an inverse association between RKIP and STAT3 expression with patient clinical outcome.
The projects in my lab are tailored to understanding the mechanisms by which RKIP is an inhibitor of metastasis and cell survival signaling and how RKIP function can be regulated. Below is a brief overview of the projects.
A) In stage II colon cancer, STAT3 has been shown to promote metastasis. We are investigating if the induction of RKIP expression can inhibit STAT3-triggered metastasis in human colon cancer cells. Future studies will explore the mechanism by which this occurs.
B) Breast cancer patients can become resistant to combination chemotherapy of paclitaxel and carboplatin. Growth factors such as estrogen or EGF can promote resistant breast cell growth by activating cell survival pathways. We are identifying the pathways that are activated in biopsied tumor samples and cell culture models. Our goal is to inhibit these pathways to restore sensitivity, possibly by the induction of RKIP expression.
C) Helicobacter pylori (H. pylori) infection is a major risk factor in the development of gastric cancer, in part, by the activation of the Jak/STAT and Nf-kB pathways and the induction of apoptosis. We hypothesized that RKIP could inhibit H. pylori-mediated gastric cancer progression by blocking these pathways. Instead our studies have indicated that H. pylori infection results in: 1) the phosphorylation of RKIP, 2) an increase in RKIP transcription mediated by phosphorylated RKIP; 3) increase in STAT3 activation; and 4) increase in H. pylori-mediated apoptosis. The mechanisms by which these unexpected events occur are an active focus of research in the lab.
Grants and AwardsPostgraduate Honors and Awards
1997-1998 Rhode Island Medical Foundation: "Novel chemotherapeutic approaches for the treatment of human prostate cancer cells resistant to 9-nitrocamptothecin".
2002-present Rhode Island Hospital and Lifespan Developmental Award. "Regulation of apoptosis in human cancer cells by the expression of RKIP".
2004-present COBRE/CCRD NIH Pilot and Junior Investigator.
Ocean State Charities Cancer Trust Fund Award, 1986-88
Pharmaceutical Manufacturers Association Foundation Advanced Predoctoral Fellowship, 1987-89
AffiliationsMember New York Academy of Sciences
The American Association for Cancer Research
1) 5P20RR017695-A1 (PI: Hixson) 07/01/2009 06/30/2014
NIH/National Center for Research Resources
Center for Cancer Research Development (COBRE)
Role: Collaborator/ Junior Investigator
The RKIP-STAT3 axis in colon cancer: Molecular profiles for prognosis and therapeutic intervention
2) R01 CA102128-05 (PI: Y.E. Chin) 06/01/2005 04/20/2011
STAT3 acetylation and deacetylation in metastasis
This study is a randomized trial of interventions to uncover STAT3 constitutive acetylation in gene regulation involved in prostate cancer metastasis.
3) R01 GM087331-02 (PI: E. Chin) 09/30/2009 08/31/2011
Acetylation-Dependent IFN Signal Transduction
Aims: To address in detail the precise mechanism of how acetylation cascade works in turning on genes involved in anti-proliferation and anti-metastasis in response to IFNa treatment in cancer cells.
1) PC093696 US Army Department of Defense (PI: Chatterjee) 7.2 calendar
Inhibition of STAT3-mediated Prostate Cancer Progression and Metastasis by RKIP
2) 1 R01 CA160298-01 NIH (PI: Chatterjee) 7.2 calender $1,696,122
Prostate cancer secreted microvesicles: modulators of tumor microenvironment.
1) Rhode Island Medical Foundation (PI: Chatterjee) 4/98-4/99
Mechanisms of Resistance to 9-nitrocamptothecin in human prostate cancer cells
2) SuperGen, Inc. (Pantazis/Chatterjee co-PIs) 6/99-5/31/01
Regulation of c-FLIP by 9-nitrocamptotheicn in human prostate cancer cells.
3) SuperGen (PI:Chatterjee) 8/1/00-7/30/01
Therapy of Cancers with 9-Nitrocamptothecin (9NC).
4) Lifespan Developmental Grant RIH (PI: Chatterjee) 2/1/03 12/31/03
"Regulation of apoptosis in human prostate cancer cells by the expression of RKIP".
5) TJ Martell Foundation (PI: Darnowski; Investigator: Chatterjee) 10/01-12/31/05
$480,000 per year
"Novel cellular and molecular targets in cancer cells".
6) Sigma Tau, Inc. (PI: Chatterjee) 8/04-12/05
Enhancement of the antineoplastic activity of Gimatecan in human tumor models.
7) RIH COBRE Center for Cancer Research Development (COBRE CCRD)
(PI: Hixson, Investigator: Chatterjee) 11/04-2/06
Regulation of RKIP in human cancers.
8) RIH project #9457 Sigma Tau, Inc., Rome Italy (Chatterjee) 12/04-12/07
The evaluation of novel camptothecin analogs in camptothecin-resistant DU145 human prostate cancer cells.
9) P20 RR17695 NIH/NCRR COBRE (PI: Hixson, Investigator:Chatterjee) 3/06-12/08
Inhibition of STAT3 signaling by RKIP.
10) W81XWH-07-1-0556, US Army Department of Defense (Chatterjee) 8/1/07-12/31/08
Inhibition of STAT3 activation by RKIP in breast cancer.
11) 3) 1R01 CA102128-01A2 NIH/NCI (Chin) 6/055/10
STAT3 Acetylation and Deacetylation in Metastasis.
12) 1) W81XWH-08-1-0516 US Army Department of Defense (Chatterjee) 10/1/08-12/31/010
Evaluation of RKIP as an antioncogene in breast cancer.