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The Bile Acid, Deoxycholic Acid, Modulates IGF-IR Function in Colon Cancer CellsMorgan, Sherif January 2009 (has links)
Deoxycholic acid (DCA) is a secondary bile acid postulated to be involved in the etiology and the progression of colorectal cancer, but its specific mechanisms are not fully understood. DCA has been shown to induce apoptosis allowing selection for apoptosis-resistant cells, which highlights the importance of understanding the mechanisms of action of DCA. Previously, it has been demonstrated that DCA perturbs the plasma membrane, leading to the activation of receptor tyrosine kinases. Because the insulin-like growth factor-1 receptor (IGF-IR), a receptor tyrosine kinase, is demonstrated to play a significant role in protecting colorectal cancer cells from apoptosis, we hypothesized that DCA modulates IGF-IR functions in colorectal cancer cells. We demonstrated that DCA induced the dynamin-dependent endocytosis of IGF-IR through both clathrin-mediated and caveolin-1-dependent mechanisms. Endocytosis of IGF-IR sensitized cells to DCA-induced apoptosis, which demonstrated that IGF-IR played a role in protecting cells against DCA-induced apoptosis. Since DCA-induced endocytosis of IGF-IR was determined to be a caveolin-1 dependent process, caveolin-1 knockdown in HCT116 (HCT116-Cav1-AS) prevented the DCA-mediated endocytosis of IGF-IR. However, we observed an increased sensitivity of DCA-induced apoptosis in the Cav1-AS cells. This suggested that caveolin-1 knockdown altered the plasma membrane dynamics such that although IGF-IR was maintained at the plasma membrane, it facilitated a pro-apoptotic signal. We demonstrated that DCA induced the activation of the pro-apoptotic p38 signaling pathway in HCT116-Cav1-AS, but not in HCT116-Mock, via IGF-IR. Inhibition of both the IGF-IR and p38 independently in HCT116-Cav1-AS significantly decreased their sensitivity to DCA-induced apoptosis. These observations demonstrated that, in a caveolin-1 dependent manner, IGF-IR played a dynamic role in the DCA-mediated apoptosis. Finally, we provided preliminary evidence demonstrating that autophagy played a central role in protecting DCA-resistant cells from DCA-induced apoptosis.Since resistance to DCA also confers apoptosis-resistance, understanding the mechanisms that lead to or prevent DCA-induced cell death is significant, since they can lead to the development of novel therapeutic strategies to sensitize apoptosis-resistant colorectal cancer cells to undergo cell death.
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An Insulin-Like Growth Factor-I Receptor Defect Associated with Short Stature and Impaired Carbohydrate Homeostasis in an Italian PedigreeMohn, Angelika, Marcovecchio, Maria Loredana, de Giorgis, Tommaso, Pfaeffle, Roland, Chiarelli, Francesco 27 July 2022 (has links)
Mutations in the insulin-like growth factor-I
(IGF-I) receptor (IGF1R) have been associated with prenatal
and postnatal growth retardation. However, little is known about potential effects of mutations in the IGF1R on carbohydrate
homeostasis. Methods: We investigated clinical, endocrine
and metabolic parameters in four family members
carrying a novel IGF1R mutation (p.Tyr387X): an 18-year-old
male (index case), his sister and two paternal aunts. Results:
All family members showed a variable degree of impairment
in prenatal growth, with birth weight standard deviation
scores (SDS) between –1.65 and –2.37 and birth length SDS
between –1.78 and –3.08. Their postnatal growth was also
impaired, with height SDS between –1.75 and –4.86. The index case presented high IGF-I levels during childhood and
adolescence and delayed bone age. The index case and his
two paternal aunts had impaired glucose tolerance (IGT) associated
with a variable degree of alterations in insulin sensitivity
and secretion. In contrast, the index case’s sister, who
had had IGT during pregnancy, showed normal glucose metabolism
but reduced insulin sensitivity. Conclusion: This is
the first study showing an association between a novel IGF1R
mutation and a variable degree of alterations in prenatal and
postnatal growth and in carbohydrate metabolism.
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