UC San Diego

Each year, more people die from lung cancer than any other cancer related death. Parathyroid hormone-related protein (PTHrP) is expressed in two-thirds of human non-small cell lung carcinoma (NSCLC), the most common form of lung cancer. Patients diagnosed with PTHrP expressing NSCLC may have better prognosis. When further studied, PTHrP positive cells increased the levels of ERK1/2 phosphorylation. Because ERK1/2 has implications on cell growth, we postulated that ERK activation in PTHrP positive cells may contribute to PTHrP's growth inhibition. To understand the role of PTHrP mediated ERK activation, an siRNA model was employed to knock down ERK1, ERK2 or ERK1 and ERK2 combined, where decreasing total ERK protein will lower phosphorylated ERK as well. ERK knockdown in ectopic PTHrP expressing cells was then tested for effects in cell proliferation and localization. ERK2 knockdown decreased proliferation in PTHrP positive cells. ERK1 knockdown increased ERK2 levels as well as increased proliferation at 72 hours, thereby suggesting a feedback mechanism between ERK1 and ERK2 in PTHrP positive cells. ERK1/ERK2 combination knockdown decreased proliferation at 72 hours, suggesting that ERK1 opposes ERK2 and inhibits proliferation. Examination of pERK cellular localization in cells ectopically expressing PTHrP demonstrates that pERK1/2 localizes to the nucleus, therefore pERK1 and pERK2 localization does not contribute to the differences in effect between isoforms. These results allude different effects between ERK isoforms where ERK2 increases proliferation and ERK1 inhibits proliferation. Therefore, PTHrP decreases proliferation through a mechanism that overpowers the pro-proliferative actions of ERK2, which may involve ERK1 activation