MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells

I. Lakshmanan, Moorthy Palanimuthu Ponnusamy, S. Das, S. Chakraborty, D. Haridas, P. Mukhopadhyay, Subodh M Lele, Surinder Kumar Batra

Research output: Contribution to journalArticle

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Abstract

MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.

Original languageEnglish (US)
Pages (from-to)805-817
Number of pages13
JournalOncogene
Volume31
Issue number7
DOIs
StatePublished - Feb 16 2012

Fingerprint

Apoptosis
Breast Neoplasms
Down-Regulation
Aurora Kinase A
Phosphorylation
Cell Proliferation
Cyclin B1
Janus Kinases
JNK Mitogen-Activated Protein Kinases
Tumor Biomarkers
Immunoprecipitation
Ovarian Neoplasms
Protein Kinases
Transcriptional Activation
Neoplasms
Transcription Factors
Tumor Necrosis Factor-alpha
Biomarkers
Ligands
Growth

Keywords

  • Aurora kinase
  • Cyclin B1
  • G2/M arrest and breast cancer
  • JNK
  • MUC16

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells. / Lakshmanan, I.; Palanimuthu Ponnusamy, Moorthy; Das, S.; Chakraborty, S.; Haridas, D.; Mukhopadhyay, P.; Lele, Subodh M; Batra, Surinder Kumar.

In: Oncogene, Vol. 31, No. 7, 16.02.2012, p. 805-817.

Research output: Contribution to journalArticle

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AU - Haridas, D.

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