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Frank A Anania - One of the best experts on this subject based on the ideXlab platform.

  • leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal transduction pathways
    Endocrine-related Cancer, 2006
    Co-Authors: Dipali Sharma, Neeraj K Saxena, Paula M Vertino, Frank A Anania
    Abstract:

    : An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a Mitogenic Agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.

Dipali Sharma - One of the best experts on this subject based on the ideXlab platform.

  • leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal transduction pathways
    Endocrine-related Cancer, 2006
    Co-Authors: Dipali Sharma, Neeraj K Saxena, Paula M Vertino, Frank A Anania
    Abstract:

    : An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a Mitogenic Agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.

Barry M. Markaverich - One of the best experts on this subject based on the ideXlab platform.

  • Disruption of male sexual behavior in rats by tetrahydrofurandiols (THF-diols)
    Steroids, 2005
    Co-Authors: Shaila K. Mani, Mary Alejandro, Andrea Reyna, Jan R. Crowley, Barry M. Markaverich
    Abstract:

    The Mitogenic Agent that disrupts male and female sexual behavior has been isolated from corncob bedding. The disrupting activity resides in an isomeric mixture of linoleic acid derivatives with a tetrahydrofuran ring and two hydroxyl groups (THF-diols) that include 9, (12)-oxy-10, 13-dihydroxtstearic acid and 10, (13)-oxy-9, 12-dihydroxystearic acid. We examined the effects of exposure of male rats to THF-diols in drinking water on several parameters of male sexual behavior. THF-diols disrupt sexual behavior in male rats by reducing mounting and intromission frequencies. The mount, intromission and ejaculatory latencies are enhanced while the ejaculatory responses are diminished. These findings suggest that the THF-diols modulate hypothalamo-pituitary axis to regulate steroid hormone-dependent male sexual behavior.

  • a novel endocrine disrupting Agent in corn with Mitogenic activity in human breast and prostatic cancer cells
    Environmental Health Perspectives, 2002
    Co-Authors: Barry M. Markaverich, Mary Alejandro, Shaila K. Mani, David Markaverich, Andrea Mitchell, Trellis Brown, Claudia Veleztrippe, Chris Murchison, Bert W Omalley, Robert E. Faith
    Abstract:

    Housing adult rats on ground corncob bedding impedes male and female mating behavior and causes acyclicity in females. The suppressive effects on ovarian cyclicity are mimicked by a Mitogenic Agent purified from the ground corncob bedding material (corn mitogen; CM), which stimulates the proliferation of estrogen receptor (ER)-positive (MCF-7 cells) and ER-negative (MDA-MD-231 cells) breast cancer cells. Purified CM does not compete for [(3)H]estradiol binding to ER or nuclear type II sites, and its effects on MCF-7 breast cancer cell proliferation are not blocked by the antiestrogen ICI-182,780. These results suggest that the active component is unlikely to be a phytoestrogen, bioflavonoid, mycotoxin, or other known endocrine-disrupting Agent that modifies cell growth via ER or type II [(3)H]estradiol binding sites. CM also stimulates the proliferation of PC-3 human prostatic cancer cells in vitro, and the growth rate of PC-3 cell xenografts is accelerated in nude male mice housed on ground corncob as opposed to pure cellulose bedding. Consequently, this endocrine-disrupting Agent in ground corncob bedding may influence behavioral and physiologic reproductive response profiles and malignant cell proliferation in experimental animals. Fresh corn (kernels and cob) or corn tortillas also contain CM, indicating that human exposure is likely; consequently, CM and/or related mitogens in corn products may influence human health and development.

  • Identification of an endocrine disrupting Agent from corn with Mitogenic activity.
    Biochemical and Biophysical Research Communications, 2002
    Co-Authors: Barry M. Markaverich, Mary Alejandro, David Markaverich, Lois Zitzow, Nancy Casajuna, Nathan Camarao, Jamal Hill, Ken Bhirdo, Robert E. Faith, John Turk
    Abstract:

    A Mitogenic Agent in corncob bedding and fresh corn products disrupts sexual behavior and estrous cyclicity in rats. The Mitogenic activity resides in an isomeric mixture of linoleic acid derivatives with a tetrahydrofuran ring and two hydroxyl groups (THF-diols) that include 9, (12)-oxy-10,13-dihydroxystearic acid and 10, (13)-oxy-9,12-dihydroxystearic acid. Synthetic THF-diols stimulated breast cancer cell proliferation in vitro and disrupted the estrous cycle in female rats at oral doses of ∼0.30 mg/kg body weight/day. Exposure to THF-diols may disrupt endocrine function in experimental animals at doses ∼200 times lower than classical phytoestrogens, promote proliferation of breast or prostate cancer, and adversely affect human health.

Robert E. Faith - One of the best experts on this subject based on the ideXlab platform.

  • a novel endocrine disrupting Agent in corn with Mitogenic activity in human breast and prostatic cancer cells
    Environmental Health Perspectives, 2002
    Co-Authors: Barry M. Markaverich, Mary Alejandro, Shaila K. Mani, David Markaverich, Andrea Mitchell, Trellis Brown, Claudia Veleztrippe, Chris Murchison, Bert W Omalley, Robert E. Faith
    Abstract:

    Housing adult rats on ground corncob bedding impedes male and female mating behavior and causes acyclicity in females. The suppressive effects on ovarian cyclicity are mimicked by a Mitogenic Agent purified from the ground corncob bedding material (corn mitogen; CM), which stimulates the proliferation of estrogen receptor (ER)-positive (MCF-7 cells) and ER-negative (MDA-MD-231 cells) breast cancer cells. Purified CM does not compete for [(3)H]estradiol binding to ER or nuclear type II sites, and its effects on MCF-7 breast cancer cell proliferation are not blocked by the antiestrogen ICI-182,780. These results suggest that the active component is unlikely to be a phytoestrogen, bioflavonoid, mycotoxin, or other known endocrine-disrupting Agent that modifies cell growth via ER or type II [(3)H]estradiol binding sites. CM also stimulates the proliferation of PC-3 human prostatic cancer cells in vitro, and the growth rate of PC-3 cell xenografts is accelerated in nude male mice housed on ground corncob as opposed to pure cellulose bedding. Consequently, this endocrine-disrupting Agent in ground corncob bedding may influence behavioral and physiologic reproductive response profiles and malignant cell proliferation in experimental animals. Fresh corn (kernels and cob) or corn tortillas also contain CM, indicating that human exposure is likely; consequently, CM and/or related mitogens in corn products may influence human health and development.

  • Identification of an endocrine disrupting Agent from corn with Mitogenic activity.
    Biochemical and Biophysical Research Communications, 2002
    Co-Authors: Barry M. Markaverich, Mary Alejandro, David Markaverich, Lois Zitzow, Nancy Casajuna, Nathan Camarao, Jamal Hill, Ken Bhirdo, Robert E. Faith, John Turk
    Abstract:

    A Mitogenic Agent in corncob bedding and fresh corn products disrupts sexual behavior and estrous cyclicity in rats. The Mitogenic activity resides in an isomeric mixture of linoleic acid derivatives with a tetrahydrofuran ring and two hydroxyl groups (THF-diols) that include 9, (12)-oxy-10,13-dihydroxystearic acid and 10, (13)-oxy-9,12-dihydroxystearic acid. Synthetic THF-diols stimulated breast cancer cell proliferation in vitro and disrupted the estrous cycle in female rats at oral doses of ∼0.30 mg/kg body weight/day. Exposure to THF-diols may disrupt endocrine function in experimental animals at doses ∼200 times lower than classical phytoestrogens, promote proliferation of breast or prostate cancer, and adversely affect human health.

I Mérida - One of the best experts on this subject based on the ideXlab platform.

  • Interleukin-2 stimulates a late increase in phosphatidic acid production in the absence of phospholipase D activation.
    FEBS Letters, 1998
    Co-Authors: D R Jones, I Flores, E Díaz, C Martinez, I Mérida
    Abstract:

    The signal transduction pathways involving phospholipid metabolism during T-cell proliferation remain partly undefined. Herein we show that interleukin-2 caused a late (> 12 h) rise in the intracellular phosphatidic acid content of CTLL-2 cells which was a consequence of the activation of the enzyme diacylglycerol kinase. No activation of phospholipase D was observed at similar times. Incubation of the cells with a recognized diacylglycerol kinase a isoform inhibitor, R59499, prior to interleukin-2 stimulation was able to block cell cycle entry, diacyglycerol kinase activation and phosphatidic acid accumulation. In contrast, when R59499 was added 3 h after interleukin-2, few or no observable effects on the above three parameters were noticed. These results suggest that the early signaling employed by IL-2 involving the alpha isoform of diacylglycerol kinase is sufficient to control the late increase in phosphatidic acid and that phosphatidic acid is a Mitogenic Agent in T-cells.

  • Interleukin‐2 stimulates a late increase in phosphatidic acid production in the absence of phospholipase D activation
    FEBS Letters, 1998
    Co-Authors: D R Jones, I Flores, E Díaz, Carlos Martínez-a, I Mérida
    Abstract:

    The signal transduction pathways involving phospholipid metabolism during T-cell proliferation remain partly undefined. Herein we show that interleukin-2 caused a late (>12 h) rise in the intracellular phosphatidic acid content of CTLL-2 cells which was a consequence of the activation of the enzyme diacylglycerol kinase. No activation of phospholipase D was observed at similar times. Incubation of the cells with a recognized diacylglycerol kinase α isoform inhibitor, R59499, prior to interleukin-2 stimulation was able to block cell cycle entry, diacyglycerol kinase activation and phosphatidic acid accumulation. In contrast, when R59499 was added 3 h after interleukin-2, few or no observable effects on the above three parameters were noticed. These results suggest that the early signaling employed by IL-2 involving the α isoform of diacylglycerol kinase is sufficient to control the late increase in phosphatidic acid and that phosphatidic acid is a Mitogenic Agent in T-cells.