Abstract:Conflict of interest: GN is chief scientific officer at RAPPTA Therapeutics, has an ownership interest (including stock, patents, etc.) in RAPPTA Therapeutics, and is a consultant/advisory board member for HERA. The Icahn School of Medicine at Mount Sinai has filed patents covering composition of matter on the small molecules disclosed herein for the treatment of human cancer and other diseases (International Application Numbers: PCT/US15/19770, PCT/US15/19764; and US Patent: US 9,540,358 B2). Mount Sinai is a… Show more
“…Consistent with previous studies, pS62-MYC staining appeared higher with expression of MYC T58A (Supplemental Fig. S 1d ) 26 , 29 , 30 . Fig.…”
Section: Resultssupporting
confidence: 92%
“…1a). In our previous work, we observed that MYC was regulated at the protein level, with high levels of pS62-MYC and low levels of pT58-MYC in breast tumor cell lines and tumor tissue relative to non-transformed mammary cell lines and adjacent normal breast tissue, respectively 26,29,30 . To investigate whether MYC is similarly post-translationally regulated in skin cancer, we obtained formalin fixed paraffin embedded (FFPE) tissue from eleven human SCC samples and six adjacent normal skin samples and analyzed these by immunofluorescence (IF) for pS62-and pT58-MYC expression using phosphorylation-specific antibodies 26 .…”
Section: Ps62-myc Is Increased and Pt58-myc Is Decreased In Clinical mentioning
cMYC (MYC) is a potent oncoprotein that is subject to post-translational modifications that affect its stability and activity. Here, we show that Serine 62 phosphorylation, which increases MYC stability and oncogenic activity, is elevated while Threonine 58 phosphorylation, which targets MYC for degradation, is decreased in squamous cell carcinoma (SCC). The oncogenic role of MYC in the development of SCC is unclear since studies have shown in normal skin that wild-type MYC overexpression can drive loss of stem cells and epidermal differentiation. To investigate whether and how altered MYC phosphorylation might affect SCC development, progression, and metastasis, we generated mice with inducible expression of MYCWT or MYCT58A in the basal layer of the skin epidermis. In the T58A mutant, MYC is stabilized with constitutive S62 phosphorylation. When challenged with DMBA/TPA-mediated carcinogenesis, MYCT58A mice had accelerated development of papillomas, increased conversion to malignant lesions, and increased metastasis as compared to MYCWT mice. In addition, MYCT58A-driven SCC displayed stem cell gene expression not observed with MYCWT, including increased expression of Lgr6, Sox2, and CD34. In support of MYCT58A enhancing stem cell phenotypes, its expression was associated with an increased number of BrdU long-term label-retaining cells, increased CD34 expression in hair follicles, and increased colony formation from neonatal keratinocytes. Together, these results indicate that altering MYC phosphorylation changes its oncogenic activity—instead of diminishing establishment and/or maintenance of epidermal stem cell populations like wild-type MYC, pS62-MYC enhances these populations and, under carcinogenic conditions, pS62-MYC expression results in aggressive tumor phenotypes.
“…Consistent with previous studies, pS62-MYC staining appeared higher with expression of MYC T58A (Supplemental Fig. S 1d ) 26 , 29 , 30 . Fig.…”
Section: Resultssupporting
confidence: 92%
“…1a). In our previous work, we observed that MYC was regulated at the protein level, with high levels of pS62-MYC and low levels of pT58-MYC in breast tumor cell lines and tumor tissue relative to non-transformed mammary cell lines and adjacent normal breast tissue, respectively 26,29,30 . To investigate whether MYC is similarly post-translationally regulated in skin cancer, we obtained formalin fixed paraffin embedded (FFPE) tissue from eleven human SCC samples and six adjacent normal skin samples and analyzed these by immunofluorescence (IF) for pS62-and pT58-MYC expression using phosphorylation-specific antibodies 26 .…”
Section: Ps62-myc Is Increased and Pt58-myc Is Decreased In Clinical mentioning
cMYC (MYC) is a potent oncoprotein that is subject to post-translational modifications that affect its stability and activity. Here, we show that Serine 62 phosphorylation, which increases MYC stability and oncogenic activity, is elevated while Threonine 58 phosphorylation, which targets MYC for degradation, is decreased in squamous cell carcinoma (SCC). The oncogenic role of MYC in the development of SCC is unclear since studies have shown in normal skin that wild-type MYC overexpression can drive loss of stem cells and epidermal differentiation. To investigate whether and how altered MYC phosphorylation might affect SCC development, progression, and metastasis, we generated mice with inducible expression of MYCWT or MYCT58A in the basal layer of the skin epidermis. In the T58A mutant, MYC is stabilized with constitutive S62 phosphorylation. When challenged with DMBA/TPA-mediated carcinogenesis, MYCT58A mice had accelerated development of papillomas, increased conversion to malignant lesions, and increased metastasis as compared to MYCWT mice. In addition, MYCT58A-driven SCC displayed stem cell gene expression not observed with MYCWT, including increased expression of Lgr6, Sox2, and CD34. In support of MYCT58A enhancing stem cell phenotypes, its expression was associated with an increased number of BrdU long-term label-retaining cells, increased CD34 expression in hair follicles, and increased colony formation from neonatal keratinocytes. Together, these results indicate that altering MYC phosphorylation changes its oncogenic activity—instead of diminishing establishment and/or maintenance of epidermal stem cell populations like wild-type MYC, pS62-MYC enhances these populations and, under carcinogenic conditions, pS62-MYC expression results in aggressive tumor phenotypes.
“…Recently, reactivation of PP2A has attracted a lot of attention as a promising approach for cancer therapy. Small molecule activators of PP2A (SMAPs) specifically activates the PP2A B56α subunit (6) and exerts anticancer effects on various cancers models such as lung cancer, breast cancer, endometrial cancer, and pancreatic neuroendocrine tumor (24)(25)(26)(27). SMAPs were engineered from phenothiazine parent compounds supporting the activation effects of PPZ on PP2A.…”
Sezary syndrome is a rare type of non-Hodgkin lymphoma. Protein phosphatase 2A (PP2A) is an important tumor suppressor whose activity is widely inhibited in a variety of tumors. Recently, reactivation of PP2A has attracted increasing attention as a promising approach for cancer therapy. Phenothiazine anti-psychotic perphenazine (PPZ) exerts antitumor effects by reactivating PP2A. The present study investigated the molecular mechanism underling the antitumor effects of PPZ in the neuroblastoma rat sarcoma oncogene (
NRAS)
-mutated Sezary syndrome cell line, HUT78. The results of the present study demonstrated that PPZ induced the dephosphorylation of Akt and ERK1/2, and triggered apoptosis in HUT78 cells. In addition, a PP2A inhibitor blocked the PPZ-mediated dephosphorylation of Akt but did not affect that of ERK1/2. The pharmacological inhibition of Akt and ERK1/2 signaling revealed that Akt activity serves an important role in the survival of HUT78 cells. The present data suggested that suppressing Akt activity by PP2A activation may be an attractive antitumor strategy for
NRAS
-mutated Sezary syndrome.
“…The combination of deregulated MYC and amplified activated HER2 accelerates the tumorigenesis, metastasis of breast cancer cells. In addition to metastasis, MYC, and HER2-overexpressed tumors are also associated with decreased survival compared with HER2-overexpression alone [ 90 ].…”
Section: Lncrna In Signaling Pathways Involved In Metastasismentioning
Breast cancer is the leading cause of cancer-related death among women. Recurrence of primary tumor and metastasis to distant body parts are major causes of breast cancer-associated mortality. The 5-year survival rate for women with metastatic breast cancer is only 25–30%. Breast cancer metastasis is a series of processes involved with EMT, invasion, loss of cell to cell adhesion, alteration in cell phenotype, extravasation, microenvironment of the tumor, and colonization to the secondary sites. Epigenetic modification is involved in the transformation of the distant stromal cell into a secondary tumor. LncRNAs, are one the key epigenetic modifiers, are the largest endogenous non-coding RNAs with approximate base-pair lengths from 200 nt to 100 kb. LncRNA plays a crucial role in breast cancer metastasis by sponging miRNA, by degrading or silencing specific mRNA, or else by targeting the enzymes and microprocessor subunits involved in the biogenesis of miRNA. LncRNA also alters the expression of several genes involved in breast cancer metastasis and modulating different cell signaling pathways. The goal of this review is to provide a better understanding of the role of lncRNA in the regulation of breast cancer metastasis. We also summarized some of the key lncRNAs that regulate the genes and signaling pathways involved in breast cancer invasion and metastasis.
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