Abstract
Lysophosphatidic acid (LPA), generated in the microenvironment of cancer cells, can drive the proliferation, invasion, and migration of cancer cells by activating G protein-coupled LPA receptors. Moreover, in cancer cells that have metastasized to bone, LPA signaling can promote osteolysis by inducing cancer cell production of cytokines, such as IL-6 and IL-8, which can stimulate osteoblasts to secrete RANKL, a key promoter of osteoclastogenesis. Indeed, in cancers prone to metastasize to bone, LPA appears to be a major driver of the expansion of osteolytic bone metastases. Activation of NADPH oxidase has been shown to play a mediating role in the signaling pathways by which LPA, as well as RANKL, promote osteolysis. In addition, there is reason to suspect that Nox4 activation is a mediator of the feed-forward mechanism whereby release of TGF-beta from bone matrix by osteolysis promotes expression of PTHrP in cancer cells, and thereby induces further osteolysis. Hence, measures which can down-regulate NADPH oxidase activity may have potential for slowing the expansion of osteolytic bone metastases in cancer patients. Phycocyanin and high-dose statins may have utility in this regard, and could be contemplated as complements to bisphosphonates or denosumab for the prevention and control of osteolytic lesions. Ingestion of omega-3-rich flaxseed or fish oil may also have potential for controlling osteolysis in cancer patients.
Highlights
Lysophosphatidic acid (LPA), generated in the microenvironment of cancer cells, can drive the proliferation, invasion, and migration of cancer cells by activating G protein-coupled LPA receptors
There is reason to suspect that Nox4 activation is a mediator of the feed-forward mechanism whereby release of TGF-beta from bone matrix by osteolysis promotes expression of parathyroid hormone-related peptide (PTHrP) in cancer cells, and thereby induces further osteolysis
Generation of lysophosphatidic acid (LPA) in the microenvironment of cancer cells has emerged as an important driver of the expansion of osteolytic metastases [1]
Summary
There is evidence that the signaling pathways stimulated by LPA1, as well as by RANKL, are dependent on activation of NADPH oxidase complexes. Further analysis has indicated that interaction of LPA with LPA1 induces internalization of the complex into early endosomes, following by assemblage and activation of an NADPH oxidase complex affiliated with the endosome that generates hydrogen peroxide within it This hydrogen peroxide oxidizes cysteine residues, forming sulfenyl groups, in certain neighboring enzymes, including Akt and the tyrosine phosphatase PTP1B. This oxidizing activity presumably is a prerequisite for the downstream activation of LPA1’s key targets, since NADPH oxidase inhibitors, as well as catalase and N-acetylcysteine (capable of reversing sulfenic acid formation), block this activation [20]. Nox and 4 [24,25]
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