This study examined the effect of 3, 9-dihydroxy-2-prenylcoumestan (pso), a furanocoumarin, on PC-3 and C4-2B castration-resistant prostate cancer (CRPC) cell lines. Pso caused significant G0/G1 cell cycle arrest and inhibition of cell growth. Molecular analysis of cyclin (D1, D2, D3, and E), cyclin-dependent kinase (cdk) (cdks 2, 4, and 6), and cdk inhibitor (p21 and p27) expression suggested transcriptional regulation of the cdk inhibitors and more significant downregulation of cdk4 than of cyclins or other cdks. Overexpression of cdk4, or silencing of p21 or p27, overcame pso-induced G0/G1 arrest, suggesting that G0/G1 cell cycle arrest is a potential mechanism of growth inhibition in CRPC cells.

Background:Autophagy is a catabolic process that has a vital role in cancer progression and treatment. Current chemotherapeutic agents, which target autophagy, result in growth inhibition in many cancer types. In this study, we examined the role of autophagy in breast cancer (BCa) patients as well as BCa cell lines.Methods:Tissue microarray was used to detect the expression of an autophagy marker, LC3B in BCa patients (normal/hyperplasia=8; grade-I=15, grade-II=84, and grade-III=27) and BCa cell lines. To modulate the activation of autophagy, we used novel herbal compound nimocinol acetate (NA) in BCa cell lines and the anticancer activity was measured by phenotypic and molecular analysis.Results:LC3B is highly expressed in tumours as compared with normal tissues. Activation of LC3B in NA-treated BCa (MCF-7 and MDA-MB-231) cells was evident as compared with other autophagy makers. Further, our results confirmed that NA-transcriptionally regulates LC3B (as confirmed by mRNA levels and reporter assay), which resulted in the formation of acidic autophagy vesicles and autolysosomes in BCa cells. Nimocinol acetate inhibited mTOR-mediated pro-survival signalling that resulted in inhibition of growth in BCa cells without affecting normal breast epithelial cells. Downregulation of LC3B expression by siRNA significantly inhibited the anticancer effects of NA in BCa cells.Conclusions:Together, our results suggest that LC3B is highly expressed in BCa tissues and increasing the threshold of LC3B activation dictates the pro-apoptotic function, which in turn, suppresses the growth of BCa cells. Nimocinol acetate could be a potential agent for treatment of BCa.

Breast cancer is a highly complex disease due to its heterogeneity in nature; that often impedes the current therapeutic options. Autophagy is a catabolic process which plays a vital role in both progressions as well as in the treatment of cancer. In fact, the role of autophagy in cancer is still unclear. Our lab is focusing on small molecules, which may induce autophagy that may result in growth arrest in breast cancer cells. In our preliminary screening studies, we have identified a small molecule, Nimocinol Acetate (NA) which induces autophagy that resulted in inhibition of growth of estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231) breast cancer cells. Molecular analysis showed the significant induction of LC-3B and ATG-3 in NA treated cells as compared to other autophagy-regulators like Atg5, Atg7, Atg12, and beclin-1, which convey the importance of ATG3 and LC3B markers in induction of autophagy. The immunofluorescence analysis confirmed the formation of acidic autophagic vesicles upon NA treatment. To further ascertain the involvement of lysosomes and autophagosomes, we specifically blocked ATG-3 and LC-3B expression by siRNA and then subjected to immunofluorescence assay. The observed results confirmed the contribution and activation of these two molecules is required for the induction of autophagy. Interestingly, no significant changes were obseverved either in the cell cycle regulation or in induction of apoptosis, which revealed that the activation of autophagy may be responsible for NA mediated growth inhibition in breast cancer cells. Currently, we are planning to conduct xenograft studies, which may suggest the in vivo efficacy and pharmacokinetic potential of NA. The present study concludes that NA could be a potential agent either alone or in combination with other chemotherapeutic agents with a novel strategy to combat breast cancer. Citation Format: Ramadevi Subramani Reddy, Pallab Pahari, Chendil Damodaran. Induction of Autophagy by a novel agent promotes the growth arrest in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1668. doi:10.1158/1538-7445.AM2013-1668

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Pancreatic cancer incidence and the associated mortality are increasing worldwide. This indicates that there is a clear lack of understanding about pancreatic cancer pathogenesis. This can be attributed to the lack of specific symptoms to diagnose the disease at an early stage. Various growth factor receptors are known to play a vital role in the development of pancreatic cancer. In the present investigation, we have attempted to target insulin-like growth factor-1 receptor (IGF-1R) due to its well-established role in progression of pancreatic cancer. RNA interference (small interfering RNA [siRNAs]) approach targeted to IGF-IR was used to study the effect of IGF-1R silencing on pancreatic cancer growth and metastasis. For this we used HPAC and PANC-1 pancreatic cancer cell lines and primary pancreatic cancer tissue array. Our results demonstrated that silencing IGF-1R remarkably inhibited pancreatic cancer growth and metastasis. Silencing IGF-1R significantly altered key signaling molecules such as PI3K, AKT, MAPK, ERK1/2, mTOR, PTEN, p70S6K, JAK2 and STAT3. Further IGF-1R silencing also reduced epithelial to mesenchymal transition (N-Cad, Notch, Snail, Slug and Vimentin). In addition, silencing IGF-1R inhibited cell viability, invasive and migratory capabilities of PANC-1 and HPAC pancreatic cancer cell lines. Colony forming ability was also drastically reduced in IGF-1R silenced cells. Flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R decreased the expression of Kras, which is altered in almost 95% of pancreatic cancers. Overall, our data clearly demonstrates the significance of IGF-1R in pancreatic cancer pathogenesis and also identifies IGF-1R as a potential target for pancreatic cancer treatment and therapy. Citation Format: Ramadevi Subramani Reddy, Arunkumar Arumugam, Sushmita Bose Nandy, Elizabeth Gonzalez, Viviana Gonzalez, Sandrine Bonkoungou, Andrew Ortega, Rajkumar Lakshmanaswamy. Role of insulin-like growth factor 1 receptor in pancreatic cancer pathogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5055. doi:10.1158/1538-7445.AM2015-5055