Nuclear Krüppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis.

Krüppel-like factor 4 (KLF4) is a transcription factor regulating cell growth and differentiation. It has been postulated as a tumor suppressor gene in several tumors including colon cancer and prostate cancer; whereas, it is activated in other tumors such as breast cancer and oropharyngeal carcinomas. To understand the significance KLF4 on clinicopathologic implications in human squamous cell carcinoma skin (SCC) progression, thirty six formalin-fixed paraffin-embedded samples of cutaneous SCC and 28 samples of Bowen's disease were stained with anti-KLF4 antibodies. A semiquantitative evaluation of the degree of staining intensity and localization of expression were analyzed and correlated with histological and clinical features. Nuclear KLF4 staining was seen in differentiated epithelium including suprabasal keratinocyte of non-lesional skin. Strong nuclear KLF4 staining was observed in tumor parts of both SCC and Bowen's disease, when compared with their non-tumor parts (p = 0.001). Increased expression of KLF4 protein and mRNA were found in squamous cell carcinoma cell line studies and fresh skin tissue respectively, using western blotting and semi-quantitative real time polymerase chain reaction (PCR). SCC with moderately and poorly differentiated tumors tend to have maturation independent (MI) staining pattern (p = 0.0004), compared to maturation dependent (MD) staining in well-differentiated tumors. Finally, constitutive nuclear KLF4 staining pattern was significantly associated with moderately and poorly differentiated tumors (p = 0.0006), and tumor metastasis (p = 0.024). We propose that KLF4 expression is associated with human skin SCC progression and metastases.

Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53.

Undecylprodigiosin (UP) is a bacterial bioactive metabolite produced by Streptomyces and Serratia. In this study, we explored the anticancer effect of UP. Human breast carcinoma cell lines BT-20, MCF-7, MDA-MB-231 and T47D and one nonmalignant human breast epithelial cell line, MCF-10A, were tested in this study. We found that UP exerted a potent cytotoxicity against all breast carcinoma cell lines in a dose- and time-dependent manner. In contrast, UP showed limited toxicity to MCF-10A cells, indicating UP's cytotoxic effect is selective for malignant cells. UP's cytotoxic effect was due to apoptosis, as confirmed by positive TUNEL signals, annexin V-binding, caspase 9 activation and PARP cleavage. Notably, UP-induced apoptosis was blocked by the pan-caspase inhibitor z-VAD.fmk, further indicating the involvement of caspase activity. Moreover, UP caused a marked decrease of the levels of antiapoptotic BCL-X(L), Survivin and XIAP while enhancing the levels of proapoptotic BIK, BIM, MCL-1S and NOXA, consequently favoring induction of apoptosis. Additionally, we found that cells with functional p53 (MCF-7, T47D) or mutant p53 (BT-20, MDA-MB-231) were both susceptible to UP's cytotoxicity. Importantly, UP was able to induce apoptosis in MCF-7 cells with p53 knockdown by RNA interference, confirming the dispensability of p53 in UP-induced apoptosis. Overall, our results establish that UP induces p53-independent apoptosis in breast carcinoma cells with no marked toxicity to nonmalignant cells, raising the possibility of its use as a new chemotherapeutic drug for breast cancer irrespective of p53 status.