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STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.

ABSTRACT: Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The mechanism by which pancreatic cancer cells resist anoikis and metastasize is not well established. Significant proportion of pancreatic cancer cells resisted anoikis when grown under anchorage-independent conditions. The cells that resisted anoikis showed higher migratory and invasive characteristics than the cells that were cultured under anchorage-dependent condition. Interestingly, anoikis-resistant cells exhibited significantly increased expression and phosphorylation of signal transducer and activation of transcription 3 (STAT3) at Tyr 705, as compared to adherent cells. AG 490 and piplartine (PL) induced significant anoikis in anoikis-resistant pancreatic cancer cells. Silencing STAT3 not only reduced the capacity of pancreatic cancer cells to resist anoikis but also reversed its invasive characteristics. Interleukin-6 treatment and overexpression of STAT3 enhanced anoikis resistance and protected the cells from PL-induced anoikis. PL-treated cells completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, untreated anoikis-resistant cells not only formed aggressive tumors but also metastasized substantially to lungs and liver when injected intravenously. Metastatic nodules formed by untreated anoikis-resistant cells in lungs exhibited significant phosphorylation of STAT3 at Tyr705. Taken together, our results established the critical involvement of STAT3 in conferring anoikis resistance to pancreatic cancer cells and increased metastasis.

SUBMITTER: Fofaria NM

PROVIDER: S-EPMC4291051 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.

Fofaria Neel M NM Srivastava Sanjay K SK

Carcinogenesis 20141119 1

Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The mechanism by which pancreatic cancer cells resist anoikis and metastasize is not well established. Significant proportion of pancreatic cancer cells resisted anoikis when grown under anchorage-independent conditions. The cells that resisted anoikis showed higher migratory and invasive characteristics than the cells that were cultured under anchorage-dependent condition. Interes ...[more]

PMID: 25411359

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Project description:Epithelial cell polarization and integration are essential to their function and loss of epithelial polarity and tissue architecture correlates with the development of aggressive tumors. Erbin is a basolateral membrane-associated protein. The roles of Erbin in establishing cell polarization and regulating cell adhesion have been suggested. Erbin is also a negative regulator in Ras-Raf-ERK (extracellular signal-regulated kinase) signaling pathway. However, the potential functions of Erbin in human cancer are basically unknown. In the present study, we show, for the first time, that loss of Erbin endows cervical cancer cells with resistance to anoikis both in vitro and in vivo and promotes the growth and metastasis of human cervical cancer xenografts in nude mice. We found that knockdown of Erbin induced the phosphorylation, nuclear translocation and transcriptional activities of signal transducer and activator of transcription factor 3 (STAT3) in cervical cancer cells. Overexpression of STAT3C or induction of endogenous STAT3 activation by interleukin (IL)-6 evidently inhibited anoikis of cervical cancer cells, whereas WP1066, a potent inhibitor of Janus-activated kinase 2 (Jak2)/STAT3, effectively blocked the effect of Erbin knockdown on cell survival under anchorage-independent conditions, indicating that loss of Erbin confers resistance of cervical cancer cells to anoikis in a STAT3-dependent manner. Interestingly, IL-6 induced STAT3 activation and Erbin expression simultaneously. Overexpression of STAT3C also significantly upregulated the level of Erbin, whereas the Jak2 inhibitor AG490 remarkably blocked not only STAT3 phosphorylation but also IL-6-induced Erbin expression. Knockdown of Erbin augmented the effects of IL-6 on STAT3 activation and anoikis resistance. In addition, by immunohistochemical analysis of Erbin expression, we demonstrate that the expression of Erbin is significantly decreased or even lost in cervical cancer tissues. These data reveal that Erbin is a novel negative regulator of STAT3, and the IL-6/STAT3/Erbin loop has a crucial role in cervical cancer progression and metastasis.

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STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.

Publications

STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.

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