Lise Tremblay

pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.

Bombesin-like peptides, including the mammalian homologue gastrin-releasing peptides, are highly expressed and secreted by neuroendocrine cells in prostate carcinoma (PCa) tissues and are likely to be related to the progression of this disease. In the present study, we show that bombesin enhances the migration of androgen-independent PCa cells (PC-3) in vitro, while not affecting their adhesion to extracellular matrix proteins. The bombesin-increased motility of PC-3 cells occurs through its receptor, and, as shown with inhibitors, it likely requires activation of both protein tyrosine kinases (PTKs) and protein kinases C (PKCs). Because the focal adhesion kinase pp125FAK plays a key role in adhesion/motility and is highly expressed in advanced PCa, we examined whether in PC-3 cells bombesin signal transduction triggers the tyrosine phosphorylation of this PTK and of associated integrins and signaling proteins likely to be present in focal adhesion plaques. pp125FAK tyrosine phosphorylation was stimulated by bombesin and mimicked by PKC activation with the tumor-promotor phorbol 12-myristate-13-acetate (PMA). Moreover, this effect of bombesin on pp125FAK tyrosine phosphorylation requires the presence of both active PKC and cytoskeleton integrity since this signal was abolished by down-regulating PKCs induced by prolonged PMA treatment or by PKC inhibition with GF 109203X, as well as by disruption of the cytoskeleton with cytochalasin D. We also show that bombesin increases the tyrosine phosphorylation of a 95-kDa protein (pp95) which was co-immunoprecipitated with the alpha v and beta (3 and 5) subunits, forming integrin receptors with alpha v in PC-3 cells. The protein pp95 is distinct from the endogenously tyrosine-phosphorylated beta3 subunit. In addition, upon bombesin treatment, the beta1, beta3 and beta5 integrin subunits co-immunoprecipitated with pp125FAK and major phosphotyrosine (pY)-containing proteins of 125 and 68-70 kDa, likely corresponding to pp125FAK and paxillin. Together our data suggest that, in addition to PKC activation, tyrosine phosphorylation of pp125FAK and integrin-associated proteins may play an important role in bombesin signaling, triggering the processes of PCa cell motility and invasion.

BACKGROUND: Patients with lung cancer often experience a reduction in exercise tolerance, muscle weakness and decreased quality of life. Although the effectiveness of pulmonary rehabilitation programs is well recognized in other forms of cancers and in many pulmonary diseases, few researchers have studied its impact in patients with lung cancer, particularly in those awaiting lung resection surgery (LRS). OBJECTIVES: To investigate the feasibility of a short, home-based exercise training program (HBETP) with patients under investigation for non-small cell lung cancer and potential candidates for LRS, and to determine the effectiveness of this program on exercise tolerance, skeletal muscle strength and quality of life. METHODS: Sixteen patients with lung cancer awaiting LRS participated in a four-week HBETP including moderate aerobic activities (walking and cycling) and muscle training performed three times weekly. Before and after the intervention, a cardiopulmonary exercise test, a 6 min walk test and the assessment of muscle strength and quality of life were performed. RESULTS: Thirteen patients completed the four-week HBETP and all the patients completed >75% of the prescribed exercise sessions. The duration of the cycle endurance test (264±79 s versus 421±241 s; P<0.05) and the 6 min walk test distance (540±98 m versus 568±101 m; P<0.05) were significantly improved. Moreover, the strength of the deltoid, triceps and hamstrings were significantly improved (∆ post-pre training 1.82±2.83 kg, 1.32±1.75 kg and 3.41±3.7 kg; P<0.05, respectively). CONCLUSION: In patients with lung cancer awaiting LRS, HBETP was feasible and improved exercise tolerance and muscle strength. This may be clinically relevant because poor exercise capacity and muscle weakness are predictors of postoperative complications.