Publications by authors named "Kimberly M Malloy"

5 Publications

  • Page 1 of 1

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer Epidemiol 2021 Oct 19;74:101978. Epub 2021 Jul 19.

MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD, 20782, USA; Georgetown, Howard Universities Center for Clinical and Translational Research, Washington, DC, 2000, USA. Electronic address:

Background: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

Methods: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

Results: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

Conclusions: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.
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http://dx.doi.org/10.1016/j.canep.2021.101978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455435PMC
October 2021

Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK) dependent pathway in human endometrial cancer cells.

PLoS One 2013 7;8(2):e55730. Epub 2013 Feb 7.

Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina, USA.

Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2) induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER)-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs), and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567109PMC
August 2013

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway.

Gynecol Oncol 2012 May 16;125(2):458-69. Epub 2012 Jan 16.

University of North Carolina, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Chapel Hill, NC, USA.

Objectives: To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines.

Methods: ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway.

Results: Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC(50) values of 1-5nM and 5-10nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index<1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line.

Conclusions: Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer.
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http://dx.doi.org/10.1016/j.ygyno.2012.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322276PMC
May 2012

Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy.

Gynecol Oncol 2010 Jan 12;116(1):92-8. Epub 2009 Oct 12.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, CB #7572, Chapel Hill, NC 27599-7572, USA.

Objectives: Obesity and diabetes are strong risk factors that drive the development of type I endometrial cancers. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce rates of cancer deaths among diabetic patients. In order to better understand metformin's anti-tumorigenic potential, our goal was to assess the effect of metformin on proliferation and expression of key targets of metformin cell signaling in endometrial cancer cell lines.

Methods: The endometrial cancer cell lines, ECC-1 and Ishikawa, were used. Cell proliferation was assessed after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3 activity. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin.

Results: Metformin potently inhibited growth in a dose-dependent manner in both cell lines (IC(50) of 1 mM). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, within 24 h of exposure. In parallel, treatment with metformin decreased phosphorylation of S6 protein, a key target of the mTOR pathway.

Conclusions: We find that metformin is a potent inhibitor of cell proliferation in endometrial cancer cell lines. This effect is partially mediated through AMPK activation and subsequent inhibition of the mTOR pathway. This work should provide the scientific foundation for future investigation of metformin as a strategy for endometrial cancer prevention and treatment.
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http://dx.doi.org/10.1016/j.ygyno.2009.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789879PMC
January 2010

CXCR1 and CXCR2 activation and regulation. Role of aspartate 199 of the second extracellular loop of CXCR2 in CXCL8-mediated rapid receptor internalization.

J Biol Chem 2007 Mar 4;282(9):6906-15. Epub 2007 Jan 4.

Julius L. Chambers Biomedical/Biotechnology Research Institute and the Department of Biology, North Carolina Central University, Durham, North Carolina 27707, USA.

CXCL8 (interleukin-8) interacts with two receptors, CXCR1 and CXCR2, to activate leukocytes. Upon activation, CXCR2 internalizes very rapidly relative to CXCR1 ( approximately 90% versus approximately 10% after 5 min). The C termini of the receptors have been shown to be necessary for internalization but are not sufficient to explain the distinct kinetics of down-regulation. To determine the structural determinant(s) that modulate receptor internalization, various chimeric and point mutant receptors were generated by progressively exchanging specific domains or amino acids between CXCR1 and CXCR2. The receptors were stably expressed in rat basophilic leukemia 2H3 cells and characterized for receptor binding, intracellular Ca(2+) mobilization, phosphoinositide hydrolysis, phosphorylation, internalization, and MAPK activation. The data herein indicate that the second extracellular loop (2ECL) of the receptors is critical for the distinct rate of internalization. Replacing the 2ECL of CXCR2 with that of CXCR1 (B(2ECL)A) or Asp(199) with its CXCR1 valine counterpart (B(D199V)A) delayed CXCR2 internalization similarly to CXCR1. Replacing Asp(199) with Asn (B(D199N)) restored CXCR2 rapid internalization. Structure modeling of the 2ECL of the receptors also suggested that Asp(199) plays a critical role in stabilizing and modulating CXCR2 rapid internalization relative to CXCR1. B(D199N) internalized rapidly but migrated as a single phosphorylated form like CXCR1 ( approximately 75 kDa), whereas B(2ECL)A and B(D199V)A showed slow and fast migrating forms like CXCR2 ( approximately 45 and approximately 65 kDa, respectively) but internalized like CXCR1. These data further undermine the role of receptor oligomerization in CXCL8 receptor internalization. Like CXCR1, B(D199V)A also induced sustained ERK activation and cross-desensitized Ca(2+) mobilization to CCR5 relative to B(D199N) and CXCR2. Altogether, the data suggest that the 2ECL of the CXCL8 receptors is important in modulating their distinct rate of down-regulation and thereby signal length and post-internalization activities.
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http://dx.doi.org/10.1074/jbc.M610289200DOI Listing
March 2007
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