Prodigiosin isolated from cell wall of Serratia marcescens alters expression of apoptosis-related genes and increases apoptosis in colorectal cancer cells

Abstract

Colorectal cancer remains often refractory to classic therapies. In consequence, the search for new anti-tumor agents with minimal toxicity is of particular interest in colon cancer treatment. Prodigiosin as a secondary metabolite of Serratia marcescens induces apoptosis in various kinds of cancer cells with low toxicity on normal cells. In the present study, we evaluated the effect of prodigiosin on proliferation and expression of apoptotic-related genes in HT-29 cells. Malignant cells were treated to various concentrations of prodigiosin and proliferation rate, survivin, Bcl-2, Bax and Bad mRNA levels, caspase 3 activation and apoptosis were evaluated by different cellular and molecular techniques. Treatment of cells with increasing concentration of prodigiosin decreased significantly cell proliferation in a dose- and time-dependent manner. Following 48-h treatment, growth rate was measured to be 77 ± 6.8, 41.3 ± 3.1 and 46 ± 6.3 % for 100, 400 and 600 nM prodigiosin, respectively, compared to untreated cells. This molecule induced 61.7, 90 and 89 % decrease in survivin mRNA level as well as 1.9-, 2.8- and 2.2-fold increase in caspase 3 activation for indicated concentrations of prodigiosin, respectively. The level of Bcl-2 mRNA was inversely proportional to Bax and Bad mRNA levels. Low mRNA levels of Bcl-2 combined with high levels of Bax and Bad mRNAs were correlated to higher apoptosis rate in treated cells. Our data suggest that prodigiosin-induced apoptosis may ascribe to Bcl-2 and survivin inhibition in HT-29 cells and these genes may provide promising molecular targets of prodigiosin. Collectively, prodigiosin may have a great potential for colorectal cancer-directed therapy.

Prodigiosin produced bySerratia marcescensinhibits expression of MMP-9 and survivin and promotes caspase-3 activation with induction of apoptosis in acute lymphoblastic leukaemia cells

“…Here, we show that prodigiosin has a negative effect on MMP-9 and survivin expression, bringing them to normal cellular levels, as well as inducing apoptosis in ALL cells. In agreement with our results, different studies showed that prodigiosin decreases survivin expression and induces caspase-3 and apoptosis in different cellular models (Soto-Cerrato et al 2004;Ho et al 2007;Hassankhani et al 2015;Yenkejeh et al 2017).…”

“…; Hassankhani et al . ) and restoration of p53 signalling pathway in cancer cells harbouring hotspot p53 mutations (Brown ) attracts too much attention to its properties. Our data and results of the above‐mentioned studies could mean an advantage of prodigiosin compound over other chemotherapeutics that need functional p53 to provoke its cytotoxic effect.…”

“…Although p53 mutations in primary leukaemia are relatively rare, up to 70% of leukaemia cells recovered after relapse contains p53 gene mutations, suggesting a critical role for p53 in leukaemia progression and resistance to chemotherapy (Imamura et al 1994). In this regard, prodigiosin with induction of apoptosis in malignant cells in a p53-independent manner (Brown 2000;Montaner and Perez-Tomas 2001;Oshiro et al 2001;Francisco et al 2007;Ho et al 2007;Hassankhani et al 2015) and restoration of p53 signalling pathway in cancer cells harbouring hotspot p53 mutations (Brown 2000) attracts too much attention to its properties. Our data and results of the above-mentioned studies could mean an advantage of prodigiosin compound over other chemotherapeutics that need functional p53 to provoke its cytotoxic effect.…”

“…Prodigiosin (Fig. 1; 2-methyl-3-pentyl-6-methoxyprodigiosene) is a natural red pigment isolated from Serratia marcescens that exerts an apoptotic effect on different kinds of cancer cells, such as hepatocellular carcinoma, colorectal cancer and acute leukaemia (Montaner et al 2000;Hassankhani et al 2015;Sam et al 2016;Yenkejeh et al 2017), with selective cytotoxicity on malignant cells and low toxicity on normal cells (Montaner et al 2000;Francisco et al 2007).…”

Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression

“…The B cell lymphoma-2 (Bcl-2) family of proteins consists of about 25 members and has been extensively studied with respect to apoptosis signaling [27]. Moreover, Bcl-2 expression has been shown to be upregulated in the most human cancers but rarely in normal tissues [27,28]. To address the molecular mechanisms of siRNA-mediated apoptosis in meningioma cells, we investigated Bcl-2 and survivin expression and demonstrated that reduced cyclin D1 expression was associated with lower antiapoptotic Bcl-2 and surviving expression.…”