Autophagy has recently been implicated in both the prevention and progression of cancer. However, the molecular basis for the relationship between autophagy induction and the initial acquisition of malignancy is currently unknown. Here, we provide the first evidence that autophagy is essential for oncogenic K-Ras (K-Ras^V12)-induced malignant cell transformation. Retroviral expression of K-Ras^V12 induced autophagic vacuole formation and malignant transformation in human breast epithelial cells. Interestingly, pharmacological inhibition of autophagy completely blocked K-Ras^V12-induced, anchorage-independent cell growth on soft agar. Both mRNA and protein levels of ATG5 and ATG7 (autophagy-specific genes 5 and 7, respectively) were increased in cells overexpressing K-Ras^V12. Targeted suppression of ATG5 or ATG7 expression by short hairpin (sh) RNA inhibited cell growth on soft agar and tumor formation in nude mice. Moreover, inhibition of reactive oxygen species (ROS) with antioxidants clearly attenuated K-Ras^V12-induced ATG5 and ATG7 induction, autophagy, and malignant cell transformation. MAPK pathway components were activated in cells overexpressing K-Ras^V12, and inhibition of JNK blunted induction of ATG5 and ATG7 and subsequent autophagy. In addition, pretreatment with antioxidants completely inhibited K-Ras^V12-induced JNK activation. Our results provide novel evidence that autophagy is critically involved in malignant transformation by oncogenic K-Ras and show that reactive oxygen species-mediated JNK activation plays a causal role in autophagy induction through up-regulation of ATG5 and ATG7.

Application of plasma medicine has been actively explored during last several years. Treating every type of cancer remains a difficult task for medical personnel due to the wide variety of cancer cell selectivity. Research in advanced plasma physics has led to the development of different types of non-thermal plasma devices, such as plasma jets, and dielectric barrier discharges. Non-thermal plasma generates many charged particles and reactive species when brought into contact with biological samples. The main constituents include reactive nitrogen species, reactive oxygen species, and plasma ultra-violets. These species can be applied to synthesize biologically important nanomaterials or can be used with nanomaterials for various kinds of biomedical applications to improve human health. This review reports recent updates on plasma-based synthesis of biologically important nanomaterials and synergy of plasma with nanomaterials for various kind of biological applications.

To prevent the development of malignancies, mammalian cells activate disposal programs, such as programmed cell death, in response to deregulated oncogene expression. However, the molecular basis for regulation of cellular disposal machinery in response to activated oncogenes is unclear at present. In this study, we show that upregulation of the autophagy-related protein, Atg5, is critically required for the oncogenic H-ras-induced autophagic cell death and that Rac1/mitogen-activated kinase kinase (MKK) 7/c-Jun N-terminal kinase (JNK) signals upregulation of Atg5. Overexpression of H-ras ^V12 induced marked autophagic vacuole formation and cell death in normal fibroblasts, which remained unaffected by a caspase inhibitor. Pretreatment with Bafilomycin A1, an autophagy inhibitor, completely attenuated H-ras ^V12 -induced cell death as well as autophagic vacuole formation. Selective production of Atg5 was observed in cells overexpressing H-ras ^V12 , and small interfering RNA (siRNA) targeting of Atg5 clearly inhibited autophagic cell death. Interestingly, inhibition of JNK or c-Jun by specific siRNA suppressed Atg5 upregulation and autophagic cell death. Moreover, inhibition of MKK7, but not MKK4, effectively attenuated H-ras ^V12 -induced JNK activation. In addition, ectopic expression of RacN17 or Rac1-siRNA effectively inhibited MKK7–JNK activation, Atg5 upregulation and autophagic cell death. These data support the notion that upregulation of Atg5 is required for the oncogenic H-ras-induced autophagic cell death in normal fibroblasts and that activation of Rac1/MKK7/JNK-signaling pathway leads to upregulation of Atg5 in response to oncogenic H-ras. Our findings suggest that in cells acquiring deregulated oncogene expression, oncogenic stress triggers autophagic cell death, which protects cells against malignant progression.

Basal-type breast cancers are among the most aggressive and deadly breast cancer subtypes, displaying a high metastatic ability associated with mesenchymal features. However, the molecular mechanisms underlying the maintenance of mesenchymal phenotypes of basal-type breast cancer cells remain obscure. Here, we report that KRAS is a critical regulator for the maintenance of mesenchymal features in basal-type breast cancer cells. KRAS is preferentially activated in basal-type breast cancer cells as compared with luminal type. By loss and gain of KRAS, we found that KRAS is necessary and sufficient for the maintenance of mesenchymal phenotypes and metastatic ability through SLUG expression. Taken together, this study demonstrates that KRAS is a critical regulator for the metastatic behavior associated with mesenchymal features of breast cancer cells, implicating a novel therapeutic target for basal-type breast cancer.