Phospholipase A2 as targets for anti-cancer drugs
Introduction
Phospholipase A2 (PLA2) are esterases that cleave glycerophospholipids at the sn-2 ester bond to release a fatty acid and lysophospholipid ([1], [2]; Fig. 1). The activity and expression of several PLA2 isoforms are increased in several human cancers [3], [4], [5], [6], [7], [8], [9], [10], [11], suggesting that these enzymes may be targets for anti-cancer drugs [5]. In order to prove this hypothesis more information is needed about the role of PLA2 in the mechanisms of carcinogenesis.
A major mechanism by which PLA2 may mediate carcinogenesis is the release of arachidonic acid, a 20-carbon fatty acid containing 4 double bonds, from glycerophospholipids. Once released, arachidonic acid is metabolized by multiple enzymes into several molecules, most of which induce cancer cell growth and proliferation in vitro[12]. In addition, PLA2 may also mediate carcinogenesis by releasing lysophospholipids (Fig. 1), which can induce cell growth via their metabolism to lysophosphatidic acid (LPA) [13], [14]. Thus, multiple mechanisms exist by which PLA2 can participate in the development of cancer.
PLA2 inhibitors are attractive anti-cancer targets as they would theoretically decrease the formation of both arachidonic acid and LPA congruently. This would eliminate the shifting of arachidonic acid to alternate pathways, possibly decreasing adverse side effects associated with arachidonic acid metabolism inhibitors [5]. However, PLA2 are a diverse family of enzymes with at least 19 different individual isoforms [2], some of which have important physiological roles [1], [15]. Thus, general inhibitors that target all PLA2 may not be practical. Therefore, more studies are needed focusing on the development of inhibition strategies for individual PLA2 isoforms. Such studies would enhance the development of PLA2 inhibitors for treatment of cancer.
Section snippets
Classification of PLA2
PLA2 are broadly defined into three different classes; secretory PLA2 (sPLA2), cytosolic PLA2 (cPLA2), and Ca2+-independent PLA2 (iPLA2) [1], [2]. sPLA2 are the oldest class of PLA2. They are found throughout nature, and were originally characterized in snake and bee venom [1]. They range in size from 13 to 19 kDa, typically require Ca2+ for their activity, and utilize histidine to hydrolyze the sn-2 ester bond of the glycerol backbone [2]. cPLA2 and iPLA2 are larger in size, typically 66–90 kDa,
PLA2 expression in human cancers
Several studies demonstrate increased expression of PLA2 in human cancers [3], [4], [5], [6], [7], [8], [9], [10], [11]. However, with the exception of Group IIA PLA2 (sPLA2), the exact roles for many of these PLA2, and their contribution towards carcinogenesis are not well understood. Further, many studies typically report the expression of a specific class of PLA2 (sPLA2, cPLA2, or iPLA2), but information regarding the expression of individual group members is lacking, with some exceptions.
Roles of PLA2 in the mechanisms of tumor formation and cancer cell growth
The roles of PLA2 in the mechanisms of carcinogenesis are diverse and somewhat controversial. They include the generation of inflammatory mediators that may to tumor formation [58], [62]. In addition, arachidonic acid and lysophospholipids can be metabolized to several molecules that induce cancer cell growth [23], [27], [28], [40], [78], [79]. Finally, the ability of select PLA2 to maintain membrane glycerophospholipids may also contribute to cancer cell growth [27], [28].
Regardless of the
Conclusion
The question can be posed if enzymes that mediate the formation of arachidonic acid and lysophospholipid metabolites are better anti-cancer targets than PLA2. This is a valid question and these pathways certainly deserve further study. However, some inhibitors of arachidonic acid metabolism, such as COX-2 inhibitors, have severe and unpredictable cardiovascular side effects [86]. This toxicity may be a result of the fact that if arachidonic acid is not metabolized by COX-2 its metabolism may be
Acknowledgements
This work was supported by a Georgia Cancer Coalition Distinguished Scholar Grant. I would like to also acknowledge Dr. Shelly Hooks and Dr. Rusty Arnold for their expertise in preparing this manuscript and Brianna Peterson, Bin Sun, and Xiaoling Zhang for their aid in proof reading.
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