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|Title:||EFFECTS OF INHIBITING THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) PATHWAY AND TELOMERASE IN BREAST CANCER CELLS||Authors:||GOPALAKRISHNAN KALPANA||Keywords:||rapamycin, mTOR, telomerase, telomeres, breast cancer, experimental therapeutics||Issue Date:||25-May-2011||Citation:||GOPALAKRISHNAN KALPANA (2011-05-25). EFFECTS OF INHIBITING THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) PATHWAY AND TELOMERASE IN BREAST CANCER CELLS. ScholarBank@NUS Repository.||Abstract:||This investigation explores the effects of rapamycin on the mTOR pathway and telomerase in breast cancer cells. The mTOR pathway, a prototypic survival pathway upregulated in many cancers, integrates various cellular signals serving as a master regulator of protein synthesis, ribosome biogenesis, autophagy, survival and proliferation. It also plays a major role in drug resistance, making mTOR an attractive anticancer target. The telomerase enzyme maintains telomere length, allowing cells to bypass the anti-proliferative barriers of senescence and crisis. Telomerase upregulation occurs in more than 90% of human cancers in addition to being critical and specific to cancer cells, making it another attractive anticancer target. The macrolide antibiotic rapamycin inhibits the mTOR pathway specifically and potently and exerts anticancer effects in a wide variety of cancers. Recent studies also showed that rapamycin inhibited telomerase and induced telomere shortening in some malignancies, although the mechanism is poorly understood. Breast cancers exhibit aberrant regulation of both the mTOR pathway and telomerase and hence may be a useful model to study the effects of rapamycin. Using this model, the investigation seeks to unravel novel mechanisms by which breast cancer cells may regulate the complex mTOR circuitry and telomerase by as yet uncharacterised mechanisms. Our results showed that breast cancer cells MCF-7 and MDA-MB-231 exhibited concurrent upregulation of phosphorylated mTOR (p-mTOR) and hTERT, albeit to different extents. In short term studies, we found that rapamycin inhibited activation of the mTOR pathway, did not modulate hTERT protein, but significantly inhibited telomerase activity in MCF-7 and MDA-MB-31 cells. Rapamycin induced G1 arrest in both cells independently of cyclin D1 and p21 expression. Rapamycin had limited effect on cell proliferation and DNA damage in MCF-7 and MDA-MB-231 cells, and led to dose-dependent loss of viability only in MCF-10A and IMR-90 cells. Altogether these results suggest that while breast cancer cells may be a useful model to study the dual inhibition of the mTOR pathway and telomerase, the activation of these two players alone cannot predict the responsiveness of these cells to short term rapamycin treatment. Long term studies showed that low dose rapamycin treatment compromised population doubling capacity of MCF-7, MDA-MB-231 and MCF-10A cells and inhibited the mTOR pathway and hTERT protein in MCF-7 and MDA-MB-231 cells. MCF-7 cells exhibited a decrease in telomerase activity and a concomitant reduction in telomere length. Interestingly, in MDA-MB-231 cells we observed upregulation of p-Akt, increase in telomerase activity and no significant change in telomere length. These data implicate novel mechanisms other than mTOR, specifically telomerase, in mediating the anticancer effects of rapamycin. Further, while rapamycin may function as a dual inhibitor of mTOR and telomerase, sustained rapamycin treatment leading to Akt activation may play a role in resistance via telomerase activation in some breast cancers. Altogether, the investigation highlights a novel mode of rapamycin action in breast cancer cells and shows that rapamycin may be a useful tool to study the molecular network linking mTOR and telomerase.||URI:||http://scholarbank.nus.edu.sg/handle/10635/28102|
|Appears in Collections:||Master's Theses (Open)|
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