c myc deregulation is involved in melphalan resistance of multiple myeloma role of pdgf bb

Oncogenes are important regulators of cancer growth and progression and their action may be modulated by proteins of the growth factor family, such as angiogenic cytokines, known to be strongly involved in neoplastic evolution. Reciprocal interactions between oncogenes and angiogenic modulators may represent, in haematological neoplasms, including multiple myeloma (MM), a possible mechanism of drug resistance. The aim of this work is to investigate in vitro and in vivo whether or not c-myc deregulation is involved in the melphalan resistance elicited by myeloma patients and consequently to clarify the role of the angiogenic factor PDGF-BB in modulating c-myc protein expression. Fifty-one MM patients on chemotherapy with melphalan were analyzed for structural alterations of the c-myc gene, c-Myc protein expression, as well as for serum PDGF-BB release. For the in vitro study, two M14-derived established cell clones, differing for the c-Myc protein expression (c-Myc low -expressing or constitutively express..

Expression profiling of microRNAs and isomiRs in conventional central chondrosarcoma

Conventional central chondrosarcoma (CCC) is a malignant bone tumor that is characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effects on CCC, treatment of most patients depends on surgical resection. This study aimed to identify the expression profiles of microRNAs (miRNAs) and isomiRs in CCC tissues to highlight their possible participation to the regulation of pathways critical for the formation and growth of this type of tumor. Our study analyzed miRNAs and isomiRs from Grade I (GI), Grade II (GII), and Grade III (GIII) histologically validated CCC tissue samples. While the different histological grades shared a similar expression profile for the top abundant miRNAs, we found several microRNAs and isomiRs showing a strong different modulation in GII + GIII vs GI grade samples and their involvement in tumor biology could be consistently hypothesized. We then in silico validated these differently expressed miRNAs in a larger chondrosarcoma public dataset and confirmed the expression trend for 17 out of 34 miRNAs. Our results clearly suggests that the contribution of miRNA deregulation, and their targeted pathways, to the progression of CCC could be relevant and strongly indicates that when studying miRNA deregulation in tumors, not only the canonical miRNAs, but the whole set of corresponding isomiRs should be taken in account. Improving understanding of the precise roles of miRNAs and isomiRs over the course of central chondrosarcoma progression could help identifying possible targets for precision medicine therapeutic intervention

Myc Prevents Apoptosis and Enhances Endoreduplication Induced by Paclitaxel

BACKGROUND: The role of the MYC oncogene in the apoptotic pathways is not fully understood. MYC has been reported to protect cells from apoptosis activation but also to sensitize cells to apoptotic stimuli. We have previously demonstrated that the down-regulation of Myc protein activates apoptosis in melanoma cells and increases the susceptibility of cells to various antitumoral treatments. Beyond the well-known role in the G1-->S transition, MYC is also involved in the G2-M cell cycle phases regulation. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have investigated how MYC could influence cell survival signalling during G2 and M phases. We used the microtubules damaging agent paclitaxel (PTX), to arrest the cells in the M phase, in a p53 mutated melanoma cell line with modulated Myc level and activity. An overexpression of Myc protein is able to increase endoreduplication favoring the survival of cells exposed to antimitotic poisoning. The PTX-induced endoreduplication is associated in Myc overexpressing cells with a reduced expression of MAD2, essential component of the molecular core of the spindle assembly checkpoint (SAC), indicating an impairment of this checkpoint. In addition, for the first time we have localized Myc protein at the spindle poles (centrosomes) during pro-metaphase in different cell lines. CONCLUSIONS: The presence of Myc at the poles during the prometaphase could be necessary for the Myc-mediated attenuation of the SAC and the subsequent induction of endoreduplication. In addition, our data strongly suggest that the use of taxane in antitumor therapeutic strategies should be rationally based on the molecular profile of the individual tumor by specifically analyzing Myc expression levels

Oligopeptides impairing the Myc-Max heterodimerization inhibit lung cancer cell proliferation by reducing Myc transcriptional activity

Deregulated CMYC gene causes cell transformation and is often correlated with tumor progression and a worse clinical outcome of cancer patients. The transcription factor Myc functions by heterodimerizing with its partner, Max. As a strategy to inhibit Myc activity, we have synthesized three small peptides corresponding to segments of the leucine zipper (LZ) region of Max. The purpose of these peptides is to occupy the site of recognition between Myc and Max located in the LZ and inhibit-specific heterodimerization between these proteins. We have used the synthesized oligopeptides in two lung cancer cell lines with different levels of Myc expression. Results demonstrate that: (i) the three peptides resulted equally effective in competing the interaction between Myc and Max in vitro; (ii) they were efficiently internalized into the cells and significantly inhibited cell growth in the cells showing the highest Myc expression; (iii) one specific peptide, only nine aminoacids long, efficiently impaired the transcriptional activity of Myc in vivo, showing a more stable interaction with this protein. Our results are relevant to the development of novel anti-tumoral therapeutic strategies, directed to Myc-overexpressing tumors

EGF-R expression in ductal breast cancer: Proliferation and prognostic implications

We studied epidermal growth factor receptor (EGF-R) expression in relation to steroid receptor status, flow cytometric DNA content and S-phase fraction (%S) in a selected case series of 129 ductal primary operable breast cancer to determine the possible role of EGF-R in prognosis assessment. EGF-R expression was positively related with proliferation activity, suggesting that EGF-R could be involved in the regulation of breast cancer cell growth. We found about 80% of highly proliferating DNA aneuploid tumors in the EGF-R positive category, while the EGF-R negative tumors showed a lower frequency of highly proliferating DNA aneuploid tumors (57%), confirming the important role of EGF-R in breast cancer aggressiveness and progression. No relationship between EGF-R expression and steroid receptor status was observed. To better understand how EGF-R and estrogen receptor (ER) operate together to stimulate breast cancer cell growth we analyzed the %S in the two groups of ER negative (ER-) and ER positive (ER+) tumors, stratifying the patients on the basis of EGF-R tumor positivity. Here breast tumor proliferation activity seems mainly to be induced by the stimulus of EGF-R, the %S values of the EGF-R negative tumors in the ER- and ER+ groups being 6.1 and 6.9%, respectively. Instead, the median %S of EGF-R positive tumors was 10% in the ER- class and 14% in the ER+ group. The analysis of the percentages of 5-year patient disease free survival were 84% for patients with EGF-R negative tumors and 61% for patients with EGF-R positive lesions, respectively. The data reported here further show the crucial role of EGF-R in breast cancer cell growth and that the EGF-R overexpression is indicative of a poor prognosis

Inhibition of leukemia cell proliferation by receptor-mediated uptake of c-myb antisense oligodeoxynucleotides.

Exposure of human leukemia HL-60 cells to an oligodeoxynucleotide complementary to an 18-base sequence (codons 2-7) of c-myb-encoded mRNA has previously been shown to result in inhibition of cell proliferation. Because HL-60 cells express high levels of transferrin receptor we adapted a DNA delivery system based on receptor-mediated endocytosis to introduce myb oligomers complexed with a transferrin-polylysine conjugate into those cells. A DNA.RNA duplex resistant to S1 nuclease digestion was detected as early as 12 hr after culture of HL-60 cells in the presence of the myb antisense/transferrin-polylysine complex. Exposure of HL-60 cells to the myb antisense/transferrin-polylysine complex resulted in rapid and profound inhibition of proliferation and loss of cell viability much more pronounced than that occurring in cells exposed to free myb antisense oligodeoxynucleotides. The transferrin-polylysine/myb sense complex or the transferrin-polylysine conjugate alone had no effect on HL-60 cell proliferation and viability. These findings indicate that myb synthetic oligodeoxynucleotides enter efficiently into HL-60 by transferrin receptor-mediated endocytosis and exert a profound biological effect. Such a delivery system could exploit other ligand-receptor interactions for the selective delivery of oncogene-targeted antisense oligodeoxynucleotides

MyoD induces apoptosis in the absence of RB function through a p21(WAF1)-dependent re-localization of cyclin/cdk complexes to the nucleus

During differentiation of skeletal myoblasts, MyoD promotes growth arrest through the induction of the cdk inhibitor p21 and the accumulation of hypophosphorylated RB protein. Myoblasts lacking RB function fail to accomplish full differentiation and undergo apoptosis. Here we show that exogenous MyoD induces apoptosis in several cell backgrounds sharing RB inactivation. This process is associated with increased levels of cell cycle-driving proteins and aberrant cell cycle progression. The inability of MyoD to induce apoptosis in a p21-null background, highlights a requirement of p21 in RB-regulated apoptosis during myogenesis. This pro-apoptotic function of p21 cannot be exerted by simple p21 over-expression, but requires the co-operation of MyoD. We also suggest that the essential aspect of p21 activity involved in such a process is related to its ability to induce the nuclear accumulation and aberrant activity of cyclin/cdk complexes. These results establish a novel link between MyoD, p21 and RB during myogenesis, providing new insights into the antagonism between muscle differentiation and loss of RB function