DEPTOR is an endogenous inhibitor of mTOR complexes, de-regulated in cancers. The present study reveals a vital role for DEPTOR in survival of cervical squamous cell carcinoma (SCC). DEPTOR was found to be overexpressed in both cervical SCC cells and tissues and it's silencing in cervical SCC cells induced apoptosis, mainly by up-regulation of p38 MAPK and by inhibiting PI3K/AKT pathway via a feed-back inhibition from mTORC1-S6K. DEPTOR silencing resulted in reduced expression of the nitric oxide synthases iNOS and eNOS, as well as increased activation of ERK1/2 and p38 MAP kinases. Activation of AKT signaling by overexpression of constitutively active-AKT (CA-AKT) failed to overcome the apoptosis caused by DEPTOR silencing. Similarly pharmacological inhibition of ERK also failed to control apoptosis. However pharmacological inhibition of p38 MAPK rescued the cells from apoptosis, indicating the major role of p38 MAPK in cell death induced by DEPTOR silencing. DEPTOR was also found to regulate ERK1/2 in an AKT dependent manner. DEPTOR knockdown induced cell death in SiHa cells overexpressing the anti-apoptotic Bcl-2 and Bcl-xL, indicating strong survival role of DEPTOR in these cells. DEPTOR overexpression activated PI3K/AKT by relieving the negative feed-back inhibition from mTORC1-S6K. DEPTOR regulation was also observed to be independent of HPV E6/E7 oncoproteins, but it might be a molecular co-factor contributing to cervical carcinogenesis. In summary, DEPTOR is found to promote survival of cervical SCC cells and its reduction induced apoptosis via differential effects on PI3K/AKT and p38 MAPK and can be a potential target in cervical SCC.
Progesterone is a biphasic hormone whose confounding role in breast cancer cells involves an initial proliferative surge, followed by sustained growth arrest. Recently we reported that progesterone induces a time- and concentration-dependent release of reactive oxygen species and thus regulates the antiproliferative activity in the breast cancer cell line. Furthermore, the expression of p27, a crucial cell cycle control protein, was regulated by binding of progesterone on progesterone receptor B, thus leading to antiproliferative signaling via multiple signaling pathways including p53, PTEN, and antioxidant systems. Here, we performed an LC-MS/MS analysis of three different breast cancer cell lines. Bioinformatics data analysis and functional classification of proteins revealed a role of progesterone in calcium signaling in MCF-7 cells, and the major differentially expressed calcium regulators were S100A11, S100A10, calreticulin, VDAC1, SERCA3, and SERCA1. Later on we confirmed it by a cell-line-based system having a calcium cameleon sensor targeted at endoplasmic reticulum and found moderate calcium efflux from endoplasmic reticulum upon progesterone treatment. Real-time PCR, Western blot, and TMRM staining confirmed the role of calcium signaling regulators VDAC1 and SERCA3 in progesterone response. Taking together all of these results with our previous studies, we suggest that progesterone, by regulating important proteins involved in calcium signaling and transport, can modulate cell proliferation and cell death. Furthermore, our research may open new avenues for the hypothesis that surgery conducted during the luteal phase of the menstrual cycle might facilitate improved patient survival.
Selective estrogen receptor modulators (SERMs) have been used in hormone related disorders, and their role in clinical medicine is evolving. Tamoxifen and raloxifen are the most commonly used synthetic SERMs, and their long-term use are known to create side effects. Hence, efforts have been directed to identify molecules which could retain the beneficial effects of estrogen, at the same time produce minimal side effects. Urolithins, the products of colon microbiota from ellagitannin rich foodstuff, have immense health benefits and have been demonstrated to bind to estrogen receptors. This class of compounds holds promise as therapeutic and nutritional supplement in cardiovascular disorders, osteoporosis, muscle health, neurological disorders, and cancers of breast, endometrium, and prostate, or, in essence, most of the hormone/endocrine-dependent diseases. One of our findings from the past decade of research on SERMs and estrogen modulators, showed that pomegranate, one of the indirect but major sources of urolithins, can act as SERM. The prospect of urolithins to act as agonist, antagonist, or SERM will depend on its structure; the estrogen receptor conformational change, availability and abundance of co-activators/co-repressors in the target tissues, and also the presence of other estrogen receptor ligands. Given that, urolithins need to be carefully studied for its SERM activity considering the pleotropic action of estrogen receptors and its numerous roles in physiological systems. In this review, we unveil the possibility of urolithins as a potent SERM, which we are currently investigating, in the hormone dependent tissues.
Pharmacological studies have shown that various species of Ficus have antiviral, antidiarrheal, antipyretic, hypolipidemic, antidiabetic, antioxidant, anticancer, antiparasitic, antiangiogenic, anti‐inflammatory, antibacterial, antiplatelet, reproductive, dermatological, immunological, endocrine, and hepato and nephron protective effects. But there is no sufficient research on biomolecules present in the leaf extract of Ficus religiosa and its mechanism of action. We have previously reported that bioavailable constituents of F. religiosa leaf extract exert photosensitizing and apoptosis‐inducing capability through the generation of intracellular reactive oxygen species on breast cancer cells. In this review, we have evaluated the expression of checkpoint proteins of G1/S and sub G0 phase with wet lab data and also have done a data mining of other research for other potential mechanistic action of the F. religiosa leaf extract.
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