Sorcin is involved during embryo implantation via activating VEGF/PI3K/Akt pathway in mice

Abstract

Our earlier studies have demonstrated the cyclic variation and also the altered expression of sorcin in endometrium during early-to-mid-secretory phase transition in women with unexplained infertility. The current study was undertaken to establish the functional role of sorcin in endometrial receptivity in mice. Results indicated that sorcin was highly expressed during the window of implantation in mice and functional blockage of sorcin caused significant reduction in number of implanted blastocyst. The receptivity markers (i.e.Integrin β3, HBEGF, IGFBP1, WNT4 and Cyclin E)) were found to be downregulated in sorcin knocked down uterine horn on day 5 as compared to untreated horn. The reduced attachment and expansion of BeWo spheroids on RL95-2 endometrial cells with sorcin knock down, in model of endometrium-trophoblast interaction further supported these findings. Uterine sorcin expression pattern during estrous cycle and in delayed implantation mice model suggested the upregulation of sorcin by estrogen. The functional blockade of sorcin induced the intracellular Ca levels in endometrial epithelial cells (EECs), which indicated that altered Ca homeostasis might be responsible for implantation failure. Sorcin silencing led to significant reduction in the expression of angiogenic factor VEGF and its downstream effector molecules i.e. PI3K, Akt and NOS. The migratory and invasive properties of HUVECs were abrogated by anti-VEGF or by adding culture media from sorcin blocked EECs, which indicated that sorcin might mediate angiogenesis during implantation. Taken together, sorcin is involved in the regulation of Ca-mediated angiogenesis via VEGF/PI3K/Akt pathway in endometrial cells and plays a crucial role in preparing the endometrium for implantation.

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

“…Sorcin increases ABCB1 expression by stimulating CREB1 phosphorylation by PKA, and binding of activated CREB1 to the cAMP response element (CRE) in the −716-−709 bp of the promoter of the ABCB1 gene [34]. Sorcin silencing was also shown to inhibit ABCB1 by suppressing ERK and Akt [76].…”

“…Dihydromyricetin (DMY), a dihydroflavonol compound with anti-oxidant, anti-inflammatory, anti-bacterial, and anti-tumor effects, is able to reverse MDR in adriamycin-dependent MD-resistant breast cancer and leukemia cell lines and in a nude mice model, and to increase adriamycin cytotoxicity, by decreasing sorcin expression (both mRNA and protein), and consequently ABCB1 levels, via ERK/Akt pathways [24,76]. DMY increases intracellular free Ca 2+ concentration, reactive oxygen species (ROS) levels, and expression of caspase 12, i.e., markers of ER stress-linked apoptosis, and regulates expression of markers of mitochondrial apoptosis, such as caspase 9, caspase 3, Bcl-2, Bax, and PARP [24].…”

“…DMY increases intracellular free Ca 2+ concentration, reactive oxygen species (ROS) levels, and expression of caspase 12, i.e., markers of ER stress-linked apoptosis, and regulates expression of markers of mitochondrial apoptosis, such as caspase 9, caspase 3, Bcl-2, Bax, and PARP [24]. Ondansetron (OND), an antiemetic drug used during tumor chemotherapy, also has a reversal effect in MDR due to sorcin expression, especially when used in combination with DMY, and restores P53 function by suppressing MDM2/MDMX, thus determining G2/M arrest and apoptosis; both DMY and OND may act by binding sorcin with high affinity [76]. It is possible that other targets may be regulated via the same ERK/Akt pathway, though the effect of DMY seems rather specific and dependent on binding to sorcin.…”

Sorcin a Potential Molecular Target for Cancer Therapy

“…Altered expression of sorcin was found in the endometrium of women with mysterious infertility during the early-to-mid-secretory phase, suggesting a possible role of sorcin in endometrial receptivity and embryo implantation. Further, it was identified that sorcin regulates the Ca 2+ -dependent angiogenesis in endometrial cells via activating VEGF/PI3K/Akt pathway and prepares the endometrium for implantation [52] .…”

Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents

“…Sorcin increases proliferation, migration, and invasion in vitro in hepatocellular carcinoma and colorectal cancer cell, and facilitates cancer growth, metastasization and EMT, via activation of ERK and/or PI3K/Akt signaling pathways [79,97] . Sorcin is also involved in the regulation of Ca 2+ -mediated angiogenesis, via the VEGF/PI3K/Akt pathway in endometrial cells and plays a crucial role in preparing the endometrium for implantation [98] .…”