4996

Telomerase, a ribonucleoprotein expressed in over 90% of all cancers, including ovarian cancer, plays an important role in cellular immortalization, survival and drug resistance. Although telomerase regulation is complex, many growth factors, including vascular endothelial growth factor (VEGF) can regulate telomerase activity in non-ovarian cancer models. Likewise, ovarian tumor growth and metastasis require VEGF-dependent angiogenesis. Since VEGF secretion by cancer cells functions in an autocrine loop to promote cancer cell growth and survival, this study examined the contribution of VEGF to regulate telomerase in ovarian cancer cells. We found that ovarian cancer cells, but not normal ovarian surface epithelial (OSE) cells, stimulated endothelial angiogenic properties, secreted in excess of 1000 pg/ml of VEGF165 and possessed the VEGF receptors, VEGFR-1 and VEGFR-2. VEGF165 also elevated telomerase activity in cancer cells, but was ineffective in telomerase-negative OSE cells. Inhibition of VEGF expression with either neutralizing antibodies or preventing VEGF receptor activation suppressed VEGF-mediated telomerase activity. VEGF increased telomerase hTERT transcription via the MAPK ERK1/2 pathway and targeted transcription binding sequences within the 976- to 578-bp regions of the hTERT promoter. Further, the potential ovarian cancer biomarker and upstream regulator of VEGF, lysophosphatidic acid (LPA), increased VEGF production and telomerase activity in all ovarian cancer cell lines examined. In addition, LPA-induced telomerase activity was abolished by concurrent treatment with the VEGF receptor inhibitor, CBO-P11, indicating that LPA-mediated telomerase activity was VEGF-dependent. In conclusion, these data represent a paradigm shift in our previously held views of VEGF solely as a regulator of endothelial cell growth and survival and identify telomerase as a novel, molecular target of LPA. Clinical modulation of the LPA/VEGF autocrine loop, then, could target and reduce telomerase activity leading to improved chemosensitivity in ovarian cancer, the leading cause of gynecological death in the US.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]