Tobacco smoke tumor promoters, catechol and hydroquinone, induce oxidative regulation of protein kinase C and influence invasion and metastasis of lung carcinoma cells.

Abstract

Cigarette smoke polyphenolic agents (catechol and hydroquinone) that generate oxidants have been shown to be tumor promoters. Furthermore, oxidants can influence protein kinase C (PKC)-mediated signal transduction. Since terpenoid tumor promoters, phorbol esters, increase invasion and metastasis by activating PKC, we have determined whether polyphenolic agents present in the cigarette smoke condensate (CSC) could also influence these events. Hydroquinone (50 atM), catechol (500 pM), or CSC (50 jpg/ml) induced an initial cytosol-to-membrane translocation of PKC in LL/2 lung carcinoma cells, followed by a later down-regulation of the enzyme. LL/2 cells treated with these CSC-related agents for a limited time (45 min) and exhibiting high membrane-assodated PKC activity, when iqjected into mice through the tail vein, produced an increase in metastatic nodules in the lungs after 20 days. However, cells treated with CSC-related agents for a prolonged period did not exhibit an increase in metastasis. Agents that decrease the rate of production of reactive oxygen species, such as catalase either alone or in combination with superoxide dismutase, and a cellpermeable iron-chelator, o-phenanthroline, inhibited CSCmediated membrane association of PKC and metastasis. Prior treatment of CSC with tyrosinase to modify polyphenols resulted in a partial loss of CSC stimulation of meta . Furthermore, a cell-permeable Ca2+ chelator and diverse PKC inhibitors, such as calphostin C, hypericin, chelerythrine, and bisindolylmaleimide, inhhbited CSC-enhanced metastasis. CSC increased in vitro tumor cell adhesion to endothellal monolayers and to reconstituted basement membrane (Matrgel) and also enhanced the invasion through Matrigel coated on the polycarbonate filters in Transwells. Al these CSC effects were found to be temporary and were blocked by the above mentioned antioxidant systems and PKC inhibitors. Thus, these results suggest that the oxidants generated by autooxidation of polyphenolic agents present in tobacco smoke increase tumor cell invasion and metastasis, at least in part by activation of Ca2+/PKC signal transduction. Conceivably, cigarette smoke constituents not only promote tumorigenesis but also may increase the spread of cancer in the body.Epidemiological studies have established a causal relationship between cigarette smoking and respiratory tract cancer (1). The most important group oftumor promoters in tobacco smoke is reported to be the catechols (2, 3). Tumor promoting hydroquinone (HQ) is also present in the cigarette smoke at a high concentration (1). Catechols from cigarette smoke are also reported to generate hydrogen peroxide and superoxide free radicals (4,5). Moreover, reactive oxygen species appear to play an important role in tumor promotion (6)(7)(8).Lung carcinoma metastasizes with a great frequency and often at an early stage while primary growth is still small and asymptomatic (9). Moreover, several clinical studies in humans presented an association between smoking and an increase in metast...

Tobacco-specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Phosphorylation of μ- and m-Calpain in Association with Increased Secretion, Cell Migration, and Invasion

“…Cigarette smoking not only initiates carcinogenesis but also promotes the spread of cancer in the body in various types of cancer including human lung and breast cancers (1,34). For example, small cell lung cancer is a refractory tumor because of its earlier dissemination, easier relapse, and distant metastases, which is found in almost all smokers (35,36).…”

“…Lung carcinoma metastasizes with a great frequency and often at an early stage, whereas primary growth is still small and asymptomatic (1). Several clinical studies in human present an association between smoking and an increase in metastasis of lung, breast and bladder cancers (1).…”

“…Several clinical studies in human present an association between smoking and an increase in metastasis of lung, breast and bladder cancers (1). Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) 1 is formed by nitrosation of nicotine and has been identified as the most potent carcinogen in cigarette smoke (2).…”

Exposure to Cigarette Tar Inhibits Ribonucleotide Reductase and Blocks Lymphocyte Proliferation

“…The potential effects of exposure to HQ or catechol cell cycle entry and progression have yet to be determined. However, HQ and catechol are known tumor promoters and have been shown to increase lung tumor invasiveness and metastasis in animal models (23,29,30). Recent reports suggest that both the M1 and M2 subunits of ribonucleotide reductase participate in cellular functions that are important for determining malignant potential (31,32), and aberrant levels of ribonucleotide reductase expression and enzyme activity have been reported in human tumors (33)(34)(35).…”

Oxidant inhibition of αLβ2 integrin adhesion: evidence for coordinate effects on conformation and cytoskeleton linkage

“…First, the adhesion modifying processes with which these compounds interact may be subject to influence by mediators naturally encountered in some physiologically extreme environments. For example, redox-modifying components of cigarette smoke alter tumor cell adhesive properties in vitro and promote corresponding changes in tumor metastasis in vivo [57]. Redox-sensitive integrin adhesion-regulatory pathways seem attractive possibilities to account for such findings.…”