| Title | Lysosomal-mitochondrial axis in zoledronic acid induced apoptosis in human follicular lymphoma cells. | | Author(s) | Mitrofan LM, Castells FB, Pelkonen J, Monkkonen J | | Institution | Faculty of Pharmacy, Department of Pharmaceutics, University of Kuopio, Finland; Biocenter Kuopio, Finland; | | Source | J Biol Chem 2009 Oct 29. | | Abstract | Bisphosphonates (BPs) are potent inhibitors of osteoclast function widely used to treat excessive bone resorption associated with bone metastases, having also anti-tumour activity. Zoledronic acid (ZOL) represents a potential chemotherapeutic agent for the treatment of cancer. ZOL is the most potent nitrogen-containing bisphosphonate (N-BPs) and it inhibits cell growth and induces apoptosis in a variety of cancer cells. Recently we demonstrated that accumulation of isopentenyl pyrophosphate (IPP) and consequent formation of a new type of ATP-analog (ApppI) after mevalonate pathway inhibition by N-BPs, strongly correlates with ZOL-induced cell death in cancer cells in vitro. In this study we show that ZOL-induced apoptosis in HF28RA human follicular lymphoma cells occurs exclusively via the mitochondrial pathway, involves lysosomes and is dependent on mevalonate pathway inhibition. In order to define the exact signalling pathway connecting them, we used modified HF28RA cell lines overexpressing either BclXL or dominant-negative caspase 9. In both mutant cells, mitochondrial and lysosomal membrane permeabilisation (MMP and LMP) were totally prevented, indicating signalling between lysosomes and mitochondria and additionally, an amplification loop for MMP and/or LMP regulated by caspase 9. Furthermore, the pan-caspase inhibitor zVAD partially inhibited both MMP and LMP, confirming involvement of caspases in the process. Moreover, a broad spectrum cathepsins inhibitor (E64) failed to suppress pro-caspase 3 activation, but partially inhibited apoptosis, suggesting that the lysosomal pathway in ZOL-induced apoptosis plays an additional/amplification role, independently of caspase 3 activation. Our findings provide a molecular basis for new strategies concomitantly targeting cell death pathways from multiple sites. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19875454 |
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