The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is partially attributed to the invasive and metastatic behavior of this disease. Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, an extracellular matrix protein secreted by cultured human keratinocytes. In addition, LAMB3 is involved in the invasive and metastatic abilities of some types of cancer, including colon, pancreas, lung, cervix, stomach, and prostate cancer, but the role and mechanism of LAMB3 in PDAC have not been previously determined. Herein, we tentatively investigated the role of LAMB3 in the malignant biological behavior of PDAC. In this study, we demonstrated that LAMB3 is upregulated in PDAC. Inhibition of LAMB3 abrogated the tumorigenic outcomes of PI3K/Akt signaling pathway activation, including those involving cell cycle arrest, cell apoptosis, proliferation, invasion and migration in vitro, and tumor growth and liver metastasis in vivo. Our results showed that LAMB3 could mediate cell cycle arrest and apoptosis in PDAC cells and alter the proliferative, invasive, and metastatic behaviors of PDAC by regulating the PI3K/Akt signaling pathway. LAMB3 may be a novel therapeutic target for the treatment of PDAC in the future.

We show here that Hsp90 inhibition effectively induces apoptosis and growth arrest in cervical carcinoma cells in vitro. Mitotic catastrophe was identified as one mechanism of cell death. In contrast, a limited efficacy of 17-DMAG was observed in subcutaneous xenograft models. Induction of a heat shock response has previously been implicated in resistance towards Hsp90 inhibition. Additional factors might be (1) an altered abundance and/or activity of primary (Hsp90) and secondary (e.g., Akt) target(s), (2) a narrow therapeutic range of 17-DMAG by oral application and (3) response-modifying factors within the tumor environment. The further development of synthetic Hsp90 inhibitors with increased therapeutic window is warranted.