Surfactant Protein D induces apoptosis in prostate cancer cells via two distinct molecular mechanisms
Gargi Thakur1, Hrishikesh Pandit1, Uday Kishore2, Taruna Madan1*
1National Institute for Research in Reproductive Health, India
2Centre for Infection, Immunity and Disease Mechanisms, Brunel University, London, UK
Surfactant protein D (SP-D), an innate immune molecule, has an indispensable role in host defense and regulation of inflammation. We reported a novel anti-cancer role of SP-D in various cell types. A recent study revealed correlation of SP-D expression in Prostate cancer tissues with increased Gleason score and tumor volume. In the present study, we elucidated the role of SP-D in prostate cancer using androgen dependent, LNCaP (p53 +/+) and androgen independent, PC3 (p53 -/-) cell lines. In accordance to our previous finding, recombinant human SP-D (rhSP-D) induced apoptosis in both these cell lines in a time and dose dependent manner. Importantly, primary normal prostate epithelial cells remained unaffected. rhSP-D upregulated phospho p53 and trancripts of Bax and reduced Bcl2 transcripts, suggesting p53 mediated apoptosis in LNCaP cells. On the contrary, rhSP-D induced apoptosis in PC3 cells was by lowering phospho ERK1/2 levels and increased BAD transcripts, a complete distinct mechanism of programmed cell dealth. Increased release of cytochrome c upon rhSP-D confirmed activation of mitochondrial intrinsic apoptotic pathway in both the cells types. Interestingly, increased SP-D expression in cancer cells than in normal prostate epithelial cells indicates immune survelliance property of SP-D in vivo. Glucocorticoids further enhanced SP-D expression in LNCaP and PC3 cells while estradiol up-regulated SP-D levels only in PC3 cells, aiding to the hormonal therapy commonly used to treat prostate cancer. Collectively, our findings reveal an integral protective role of SP-D in prostate cancer mediated by two distinct apoptotic mechanisms. Further, pathway analysis, interactome study and effects on prostate cancer tissue will lead to further insights in understanding SP-D mediated immunotherapy for prostate cancer.
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