Suppression of Tobacco Carcinogen-Induced Lung Tumorigenesis by Aerosol-Delivered Glycerol Propoxylate Triacrylate-Spermine Copolymer/Short Hairpin Rab25 RNA Complexes in Female A/J Mice

Abstract

Our results strongly confirm the tumorigenic role of Rab25 in tobacco carcinogen-induced lung cancer and hence demonstrate aerosol delivery of shRab25 as a therapeutic target for lung cancer treatment.

Rabs Mediated Membrane Trafficking in Cancer Progression

“…Rab25 has been documented in the alternation of expression of apoptotic molecules; where Rab25 was found to reduce pro-apoptotic proteins BAX and BAK in ovarian cancer [28], and its knockdown tends to reduce anti-apoptotic molecule Bcl-2 in tobacco carcinogen-induced lung cancer [48]. Hence, it can be concluded that, the epithelial-specific protein, Rab25, boosts cancer progression by stimulating growth promoting signaling pathways and suppressing apoptotic cell death.…”

Rab 25: Oncogenes and Tumor Suppressive of Cancer

“…Research shows that Rab 25 can promote the in vitro proliferation of renal cell carcinoma cells [21], hepatocellular carcinoma cells [13], and skin squamous cell carcinoma [22]. When levels of Rab 25 is reduced in lung cancer caused by tobacco carcinogen, tumor growth is reported to be restricted [23]. Conversely, ectopic expression of Rab 25 was reported to promote proliferation of breast cancer cells [24] and ovarian cancer cells [25].…”

Rab25 GTPase: Functional roles in cancer

“…Moreover, Rab25 suppressed apoptotic cell death by reducing the expression of pro-apoptotic molecules, BAX and BAK, in ovarian cancer [ 12 ]. Knockdown of Rab25 was found to reduce anti-apoptotic protein, Bcl-2, in tobacco carcinogen-induced lung cancer [ 50 ]. Taken together, activation of growth-stimulating signaling pathways and suppression of apoptotic cell death pathways mediate the effect of Rab25 on enhancing cancer progression.…”

“…Suppression of both in vitro cell growth and in vivo xenograft development were observed after knockdown of Rab25 in glioblastoma multiforme cells (U87MG) [ 21 ] and breast cancer cells (MCF7) [ 58 ]. Knockdown of Rab25 was reported to inhibit tumor growth in tobacco carcinogen-induced lung cancer model [ 50 ]. Conversely, ectopic overexpression of Rab25 was found to induce in vitro cell growth of breast cancer cells (MCF7) [ 12 , 58 ] and ovarian cancer cells (A2780, DOV13, HEY, OCC1) [ 12 ].…”

“…Elevated expression of Rab25 decreased UV-induced apoptosis in ovarian cancer [ 12 ]. Knockdown of Rab25 was reported to increase apoptosis in ovarian cancer cells [ 60 ] and tobacco carcinogen-induced lung cancer model [ 50 ]. Moreover, Rab25 down-regulation was reported to induce autophagic cell death in ovarian cancer from two independent research studies [ 60 , 61 ].…”