Investigation Of Molecular Mechanisms Of Cancer Progression,Drug Resistance And Approaches For Cancer Suppression

Human cancer is a severe malignancy and global health problem.Chemotherapy has been considered promising therapy for the treatment of human cancers.However,prolong treatment of chemotherapy leads to clonal evolution owing to novel mutations and results in resistance in response to novel anti-cancer drugs.Medermycin,as a prominent member of benzoisochromanequinones,possesses strong antitumor activity and is biosynthesized under the control of a 29-ORFcontaining biosynthetic gene cluster.Most of ORFs in this gene cluster have not been characterized,including a small protein encoding gene med-ORF 10,proposed to play a regulatory role in biosynthesis of medermycin in an unknown mode.In our first experiment,we reported the expression,protein preparation,crystallization and preliminary X-ray diffraction analyses of Med-ORF10 of the wild type Streptomyces strain.These studies provide evidences for the functional Med-ORF10 protein in Streptomyces strains and facilitate our further investigation.Mitochondria dynamic is also strongly associated with cancer progression and suppression through fission and fusion.Mitochondrial fission causes cancer progression whereas mitochondrial fusion suppresses cancer.Mitochondrial fission and fusion are mediated by various GTPases in outer mitochondrial membrane,particularly mitofusin-1(Mfn-1)and mitofusin-2(Mfn-2),which induces fusion,and dynamin-related protein(Drp-1),which induces fission.In our second experiment,we explored the potential role of SPRYD4 gene in cancer suppression through modulating mitochondrial dynamics.We found that overexpression of SPRYD4 causes decreased fission and increased fusion in cancer cells via unbalancing expression of fission and fusion regulators.Overexpressed SPRYD4 HeLa cells demonstrated a decrease in Drp-1 and an increase in Mfn-1 and Mfn-2 as compared to WT HeLa cells.Furthermore,overexpression of SPRYD4 suppresses cancer cell proliferation and energy production.Loss of SPRYD4 compromises mitochondrial fragmentation in cancer cells.Taken together,these findings suggested that SPRYD4 plays an important role in the suppression of cancer progression through modulating mitochondrial dynamics.Currently,impairing energy metabolism has been viewed as an effective and promising anticancer strategy.Flavaglines are potent anticancer natural products that inhibit cancer cells proliferation and viability at a nanomolar concentration without being toxic to non-cancer tissues.In our third experiment,we explored the effects of FL3,a synthetic flabagline,on cancer energy metabolism.Results show that FL3 inhibited cancer cell proliferation by inhibiting energy production and inducing cell cycle arrest.In conclusion,this study has explored molecular mechasnisms of cancer progression drug resistance and novel approaches for overcoming drug resistance to novel anti-cancer drugs.This study will open a new window in improving currently used therapeutic tools and developing new strategies for treating human cancers.