Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum.
Ovarian cancer is the most lethal gynecological malignancy. Cisplatin and its derivatives are first-line chemotherapeutics, and their resistance is a major hurdle in successful ovarian cancer treatment. Understanding the molecular dysregulation underlying chemoresistance is important for enhancing therapeutic outcome. Here, we review two established pathways in cancer chemoresistance. p53 is a major tumor suppressor regulating proliferation and apoptosis, and its mutation is a frequent event in human malignancies. The PI3K/Akt axis is a key oncogenic pathway regulating survival and tumorigenesis by controlling several tumor suppressors, including p53. The interplay between these pathways is well established, although the oncogenic phosphatase PPM1D adds a new layer to this intricate relationship and provides new insights into the processes determining cell fate. Inhibition of the PI3K/Akt pathway by functional food compounds as an adjunct to chemotherapeutics may tip the balance in favor of apoptosis rather than survival, enhancing therapeutic efficacy, and reducing side effects.
Department of Cellular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Ahmed Y
AY
Ali
Lee
L
Farrand
Ji Young
JY
Kim
Sanguine
S
Byun
Jeong-Yong
JY
Suh
Hyong Joo
HJ
Lee
Benjamin K
BK
Tsang
D000818:Animals; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005527:Food, Fortified; D055951:Functional Food; D006801:Humans; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000071636:Protein Phosphatase 2C; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C