Role of MAP-kinases in genotoxicities induced by lead and benzo[a]pyrene in human non-small-cell lung adenocarcinoma cell line

• Main Authors: Yun-Wei Lin, 林芸薇
• Other Authors: Jia-Ling Yang
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/68059051083975414673

碩士 === 國立清華大學 === 生命科學系 === 87 === Abstract Environmental toxicants may induce signal transduction pathways to interfere with cell growth, differentiation, apoptosis, DNA damage and repair, and genotoxicity. These signals are therefore highly associated with carcinogenesis induced by environmental toxicants. This thesis investigated the activation of ERK, JNK and p38 MAP-kinases by lead(II) and/or benzo[a]pyrene in a human non-small-cell lung adenocarcinoma cell line, CL3. The roles of these MAP-kinases in cytotoxicities and genotoxicities induced by lead and/or benzo[a]pyrene were also studied. Low cytotoxic lead(II) persistently activated ERK phosphorylation, whereas it did not induce JNK and p38. Inhibiting MEK, the ERK upstream signal molecule, by PD98059 enhanced the cytotoxicity caused by high concentrations of lead(II). The result suggested that ERK pathway activated by lead(II) may participate in preventing cell from cytotoxicity or stimulating cell proliferation. In contrast, benzo[a]pyrene markedly activated p38 but not JNK or ERK pathways. Inhibiting p38 activation by SB202190 significantly reduced the cytotoxicity and mutation frequency of the hprt gene induced by benzo[a]pyrene. The result suggested that p38 activation is positive correlated to the cytotoxicity and genotoxicity induced by benzo[a]pyrene. Pretreatment of cells with lead(II) markedly enhanced the cytotoxicity induced by benzo[a]pyrene. This pretreatment also synergistic activated the p38 phosphorylation, but the ability of lead(II) to activate ERK was diminished. The result suggested that lead(II) co-cytotoxicity is positive correlated to the p38 activation and ERK inactivation. On the other hand, lead(II) pretreatment could enhance the cytotoxicity and the p38 activation induced by UVC light. Together, results showed here indicate that p38 pathway may participate in cytotoxicity or inhibiting cell proliferation by environmental toxicants. Lead(II) may exert its co-genotoxicity by synergistic activation of the p38 pathway.