Rab
proteins are
GTPases involved in all stages of vesicular transport and membrane fusion in mammalian cells. Individual Rab
proteins localize to specific cellular organelles and regulate a specific membrane trafficking pathway. Recent studies suggest an important role for Rab
proteins in
cancer. Rab3
isoforms (Rab3A, Rab3B, Rab3C, and Rab3D) are expressed almost exclusively in neurons and secretory cells. In this review, the role of Rab3
isoforms in a variety of
tumor types is discussed. Of the four Rab3
isoforms, Rab3D has been studied most extensively in
cancer cells and this
isoform appears to play an oncogenic role in breast, colon, esophageal, skin, and
brain tumors. Overexpression of Rab3A and Rab3C was observed in
gliomas and
colon cancers, respectively. Increased expression of the Rab3
isoforms is related to increased proliferation, migration, and invasiveness. Moreover, high Rab3
isoform levels are often associated with decreased survival and advanced pathological stage in clinical samples. Rab3
isoform-dependent activation of the AKT pathway has been observed in several studies. Although the effects of Rab3
isoforms on
cancer cell growth and function have been examined in many
tumor types, a number of important questions remain. Are the Rab3-positive vesicles in
cancer cells actually secretory in nature? If so, are the contents of these vesicles secreted in a regulated or constitutive manner? How does Rab3-regulated secretion affect cellular signaling and
tumor growth? Finally, can Rab3
isoforms be therapeutically manipulated in
cancer cells? The fact that knockout of a single Rab3
isoform does not affect viability, at least in mouse models, suggests that targeting of these
proteins may be a safe and effective treatment strategy for
tumor cells expressing any of the Rab3
isoforms.