Therapeutic Uses of HSP90 Inhibitors in Non-Small Cell Lung Carcinoma (NSCLC).
Akram Anam,Khalil Sara,Halim Sobia Ahsan,Younas Hooria,Iqbal Sadaf,Mehar Saima
Current drug metabolism
BACKGROUND:Non-Small Cell Lung Carcinoma is one of the major cause of morbidity and mortality worldwide with an incidence rate of 1.3 million cases per year. Heat shock protein 90 (HSP90) is a promising drug target in cancer treatment. HSP90 is required to activate numerous eukaryotic proto-oncogenic protein kinases, hence play a prominent role in cancer. METHOD:We reviewed fifty-five articles to highlight the importance of HSP90 in NSCLC and the recent developments of its inhibitors. RESULTS:This review showed that HSP90 inhibitors i.e. Ganestespib have shown great potential in the treatment of non-small cell lung carcinoma (NSCLC). Different HSP90 inhibitors has been designed till date that acts as effective drugs in tumour suppression. However, the utility of these drugs has been limited due to several drawbacks including hepato-toxicity, poor solubility, and poorly tolerated formulations. CONCLUSION:The goal of this review is to present the data in support of use of HSP90 inhibitors in NSCLC and to provide an overview of the on-going clinical trials involving new-generation HSP90 inhibitors.
Secretion of a low-molecular-weight species of endogenous GRP94 devoid of the KDEL motif during endoplasmic reticulum stress in Chinese hamster ovary cells.
Traffic (Copenhagen, Denmark)
GRP94 (glucose-regulated protein 94) is a well-studied chaperone with a lysine, aspartic acid, glutamic acid and leucine (KDEL) motif at its C-terminal, which is responsible for GRP94 localization in the endoplasmic reticulum (ER). GRP94 is upregulated during ER stress to help fold unfolded proteins or direct proteins to ER-associated degradation. In a previous study, engineered GRP94 without the KDEL motif stimulated a powerful immune response in vaccine cells. In this report, we show that endogenous GRP94 is naturally secreted into the medium in a truncated form that lacks the KDEL motif in Chinese hamster ovary cells. The secretion of the truncated form of GRP94 was stimulated by the induction of ER stress. These truncations prevent GRP94 recognition by KDEL receptors and retention inside the cell. This study sheds light on a potential trafficking phenomenon during the unfolded protein response that may help understand the functional role of GRP94 as a trafficking molecule.