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Calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2), an alternative to curcumin in head and neck squamous cell carcinoma.

ABSTRACT: Curcumin has been shown to exhibit anti-neoplastic effects. However, due to its poor bioavailability, use of curcumin as an anti-cancer drug is limited. It is thus necessary to identify molecules that could be targeted using anti-cancer agents as alternatives to curcumin. For this, it is important to understand the underlying signaling pathways mediating the anti-neoplastic effects of curcumin. We carried out phosphoproteomic analysis (TiO2-based enrichment of Ser/Thr kinases) of head and neck cancer cell line, CAL27 treated with curcumin to identify curcumin mediated signaling pathways. This resulted in the identification of 5921 phosphopeptides (phosphosite probability≥75%) corresponding 1,878 proteins. Of these, 275 and 335 phosphopeptides corresponding to 183 and 242 proteins (≥2.0-fold) were found to be hyper- and hypo-phosphorylated respectively, in response to curcumin treatment

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Oral Epithelium

DISEASE(S): Oral Cavity Cancer

SUBMITTER: Aditi Chatterjee

LAB HEAD: Aditi Chatterjee

PROVIDER: PXD007256 | Pride | 2022-03-03

REPOSITORIES: Pride

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			Action	DRS
	CAL27_Curcumin_2SILAC_pSTY_All_PD1.4_Sequest_Mascot_121713.msf	Msf
	CAL27_Curcumin_2SILAC_pST_01_R.raw	Raw
	CAL27_Curcumin_2SILAC_pST_02.raw	Raw
	CAL27_Curcumin_2SILAC_pST_03.raw	Raw
	CAL27_Curcumin_2SILAC_pST_04.raw	Raw

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Project description:Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers with high mortality rate. Smoking is one of the established risk factors of ESCC. However, there is limited data on molecular alterations associated with cigarette smoke exposure in esophageal cells. Understanding the effects of cigarette smoke on esophageal squamous epithelial cells at a molecular level would lead to a better understanding of the pathobiology of ESCC which has implications for identification of early biomarkers and therapeutic targets. To investigate the effect of cigarette smoke exposure, we developed a cell line model where Het1A cells (non-neoplastic human esophageal epithelial cells) were chronically treated with cigarette smoke condensate (CSC) for 2 months, 4 months, 6 months and 8 months. We carried out comparative proteomic, phosphoproteomic and whole exome sequencing analyses on CSC treated and untreated cells. Increased cell proliferation and invasion of Het1A cells was observed after chronic exposure to cigarette smoke. Using quantitative proteomic and phosphoproteomic analyses, we identified 56 proteins and 296 phosphoproteins that showed differential expression. Bioinformatics analysis of differentially expressed proteins and phosphoproteins showed enrichment of molecules involved in DNA damage response pathway. Whole exome sequencing (WES) of CSC treated and untreated cells also revealed mutations and copy number alterations in genes associated with DNA damage response. By correlating WES, proteomic and phosphoproteomic results, we observed potential loss of function in HMGN2 and MED1 that were reported as potential tumor suppressors and are known to play important role in DNA damage response. We also observed decreased expression of HMGN2 in tissue section of ESCC. Overexpression of HMGN2 and MED1 lead to decreased proliferative and invasive ability of CSC treated cells. These findings suggest that cigarette smoke affects genes and proteins associated with DNA damage response pathways which might play a vital role in development of ESCC.

Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.

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Calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2), an alternative to curcumin in head and neck squamous cell carcinoma.

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