The SKBR3 Cell-Membrane Proteome: Role in Aberrant Cancer Cell Proliferation and Resource for Precision Medicine Applications

Mapping Intimacies ◽

10.1101/2021.10.24.465642 ◽

2021 ◽

Author(s):

Arba Karcini ◽

Iulia M Lazar

Keyword(s):

Cell Proliferation ◽

Cell Membrane ◽

Precision Medicine ◽

Cancer Cell ◽

Critical Role ◽

Immune Recognition ◽

Cancer Cell Proliferation ◽

Membrane Proteome ◽

Her2 Breast Cancer ◽

Cellular Environment

The plasma membrane proteome resides at the interface between the extra- and intra-cellular environment and through its various roles in signal transduction, immune recognition, nutrient transport, and cell-cell and cell-matrix interactions plays an absolutely critical role in determining the fate of a cell. Our work was aimed at exploring the landscape of the cancer cell-membrane proteome responsible for sustaining uncontrolled cell proliferation, and its intrinsic resources for enabling detection and therapeutic interventions. SKBR3/HER2+ breast cancer cells were used as a model system and mass spectrometry for characterizing the proteome. The number of identified cell-membrane proteins exceeded 2,000, with ~1,300 being matched by two or more unique peptides. Classification in four major categories, i.e., proteins with receptor or enzymatic activity, CD antigens, transporters, and cell adhesion proteins, uncovered overlapping roles in biological processes that drive cell growth, apoptosis, differentiation, immune response, adhesion and migration, as well as capabilities for signaling crosstalk and alternate pathways for proliferation. The large number of tumor markers (>50) and putative drug targets (>100) exposed a vast potential for yet unexplored detection and targeting opportunities, whereas the presence of 15 antigen immunological markers enabled an assessment of epithelial, mesenchymal or stemness characteristics. Serum-starved cells displayed altered processes related to mitochondrial OXPHOS/ATP synthesis, protein folding and localization, while serum-treated cells exhibited attributes that support tissue invasion and metastasis. Altogether, our findings advance the understanding of the biological triggers that sustain aberrant cancer cell proliferation, survival and development of resistance to therapeutic drugs, and reveal the vast innate opportunities for guiding immunological profiling and precision medicine applications aimed at target selection or drug discovery.

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FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner

Cell Death Discovery ◽

10.1038/s41420-021-00724-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Guanwen Zhou ◽

Keqiang Yan ◽

Jikai Liu ◽

Lijian Gao ◽

Xianzhou Jiang ◽

...

Keyword(s):

Cell Proliferation ◽

Bladder Cancer ◽

Cancer Cell ◽

Cancer Progression ◽

Prognostic Biomarker ◽

Critical Role ◽

Bladder Cancer Cell ◽

Dependent Manner ◽

Cancer Cell Proliferation ◽

Aberrant Expression

AbstractThe aberrant expression of fat mass and obesity-associated protein (FTO) has been confirmed to be associated with a variety of cancers and participates in the regulation of multiple biological behaviours. FTO plays an oncogenic role in bladder cancer, but few studies have focused on how FTO promotes bladder cancer progression by regulating miRNA synthesis. Here, we confirmed that FTO expression was significantly increased in bladder cancer and was associated with a poor prognosis. FTO overexpression promoted bladder cancer cell proliferation, whereas FTO knockdown inhibited bladder cancer cell proliferation. We also demonstrated that FTO promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathways. Taken together, our work revealed that FTO plays a critical role in bladder cancer and could be a potential diagnostic or prognostic biomarker for this disease.

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Sodium-Dependent Glucose Transporter 1 (SGLT1) Stabled by HER2 Promotes Breast Cancer Cell Proliferation by Activation of the PI3K/Akt/mTOR Signaling Pathway in HER2+ Breast Cancer

Disease Markers ◽

10.1155/2020/6103542 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Jinlu Wang ◽

Hongfei Ji ◽

Xingjian Niu ◽

Lei Yin ◽

Yiran Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Mtor Signaling ◽

Her2 Status ◽

Cancer Cell Proliferation ◽

Breast Cancer Patients ◽

Breast Cancer Cell Proliferation ◽

Her2 Breast Cancer

Aerobic glycolysis is a hallmark of tumor cells. SGLT1 plays a vital role in glucose metabolism. However, whether SGLT1 could promote cell growth and proliferation in breast cancer remains unclear. Here, we investigated the expression of SGLT1 in breast cancer and examined its role in malignant behavior and prognosis. Further, we examined the SGLT1 expression in breast cancer tissues and its relationship with clinicopathologic characteristics. We clarified that SGLT1 was overexpressed in HER2+ breast cancer cell lines and was affected by HER2 status. We further found that SGLT1 affected breast cancer cell proliferation and patient survival by mediating cell survival pathway activation. SGLT1 was overexpressed in HER2+ breast cancers and associated with lymph node metastasis and HER2+ status. Inhibition of HER2 decreased SGLT1 expression, and the extracellular acidification rate was also reduced in the UACC812 and SKBR3 cell lines. These changes could be reversed by proteasome inhibitor treatment. Knockdown of SGLT1 blocked PI3K/Akt/mTOR signaling, thereby inhibiting cell proliferation. Further, we demonstrated that high SGLT1 was significantly correlated with shorter survival in all breast cancer patients and specifically in HER2+ breast cancer patients. Therefore, we conclude that SGLT1 is overexpressed in HER2+ breast cancer, thereby promoting cell proliferation and shortening survival by activating PI3K/Akt/mTOR signaling. This study submits that SGLT1 is promising not only as a novel biomarker of HER2+ breast cancer subtype but also as a potential drug target.

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APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF

International Journal of Molecular Sciences ◽

10.3390/ijms21103586 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3586 ◽

Cited By ~ 1

Author(s):

Yoo-Duk Choi ◽

Ji-Yeon Jung ◽

Minwoo Baek ◽

Sheema Khan ◽

Peter I. Song ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Line ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Critical Role ◽

Therapeutic Drug ◽

Cancer Cell Proliferation ◽

Aberrant Expression ◽

Pancreatic Carcinoma Cell Line

Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.

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