Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis

Abstract

Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer.

MicroRNA‐135a‐3p as a promising biomarker and nucleic acid therapeutic agent for ovarian cancer

“…(24)(25)(26)(27)(28)(29)(30) In prostate cancer cells, miR-135a-3p was shown to mimic the enhanced apoptosis induced by death receptor 5 with respect to increased poly(ADP-ribose) polymerase cleavage, Bax expression, and the number of TUNEL-positive cells following cotreatment with tanshinone I and TRAIL. (32) Our present study indicates that miR-135a-3p may also have antitumor activities in ovarian cancer. Human miR-135a is encoded by two genes located on different chromosomes that produce identical active sequences (chromosomes 3 and 12 for miR-135a1 and miR-135a2, respectively).…”

“…Many studies have investigated the relationship between miR-135a-5p and cancer, (24)(25)(26)(27)(28)(29)(30) but have not examined miR-135a-3p. (31,32) MicroRNA-135a-5p has often been reported to function as a potential tumor suppressor. (24)(25)(26)(27)(28)(29)(30) In prostate cancer cells, miR-135a-3p was shown to mimic the enhanced apoptosis induced by death receptor 5 with respect to increased poly(ADP-ribose) polymerase cleavage, Bax expression, and the number of TUNEL-positive cells following cotreatment with tanshinone I and TRAIL.…”

Tanshinone IIA induces intrinsic apoptosis in osteosarcoma cells both in vivo and in vitro associated with mitochondrial dysfunction

“…reported that endothelial expression of Drp1 and Fis1 increased and Opa1 decreased in diabetes mellitus with alterations in mitochondrial networks, ROS production, endothelial nitric oxide synthase (eNOS) activation, and cyclic guanosine monophosphate (cGMP) production36. Our findings with decrease in tumor size and IHC analysis of CD31 suggested that Tan IIA might inhibit angiogenesis associated with down regulation of ROS3738 through mitochondrial dynamics. In the present study, we further confirmed that Tan IIA indeed reduced the levels of Mfn-1, Mfn-2 and Opa-1 and increased the levels of Drp-1 in both osteosarcoma 143B cells and 143B cell xenograft mice.…”

Auraptene Induces Apoptosis via Myeloid Cell Leukemia 1-Mediated Activation of Caspases in PC3 and DU145 Prostate Cancer Cells

“…Although radical prostatectomy, chemotherapy, radiotherapy, high‐intensity focused ultrasound, and hormonal therapy surgery have been used for prostate cancer management, prostate cancer therapy is still limited because of chemo‐resistance and toxicity of anticancer agents. Thus, recently, many natural compounds such as curcumin (Cheng et al ., ), resveratrol (Alkhalaf, , ; Aluyen et al ., ; Whitlock et al ., ), capsaicin (Jung et al ., ), brazilin (Kim et al ., ), tanshinone I (Shin et al ., ), tanshinone IIa (Yun et al ., ), ursolic acid (Song et al ., ), coumestrol (Cho et al ., ), isothiocyanates (Gupta et al ., ), ginkgetin (You et al ., ), and auraptene (de Medina et al ., ) became attractive because of their efficacy and less toxicity.…”

“…Although radical prostatectomy, chemotherapy, radiotherapy, highintensity focused ultrasound, and hormonal therapy surgery have been used for prostate cancer management, prostate cancer therapy is still limited because of chemo-resistance and toxicity of anticancer agents. Thus, recently, many natural compounds such as curcumin (Cheng et al, 2013), resveratrol (Alkhalaf, 2007a(Alkhalaf, , 2007bAluyen et al, 2012;Whitlock et al, 2011), capsaicin (Jung et al, 2014), brazilin , tanshinone I (Shin et al, 2014), tanshinone IIa (Yun et al, 2013), ursolic acid (Song et al, 2012), coumestrol (Cho et al, 2014), isothiocyanates (Gupta et al, 2014), ginkgetin (You et al, 2013), and auraptene (de Medina et al, 2010) became attractive because of their efficacy and less toxicity. Auraptene (7-geranyloxycoumarin) contained in Ferula and Citrus fruit (Soltani et al, 2010) has been shown to have antiinflammatory, anti-protozoal, anti-fungal, anti-bacterial, anti-oxidative, and immunomodulatory effects (Epifano et al, 2008;Takahashi et al, 2011).…”