Abstract
Ovarian cancer (OvCa), while accounting for only 3% of all women’s cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.
Highlights
Ovarian cancer (OvCa) is the most lethal cancer of the female reproductive system and the fifth leading cause of cancer death among women
We found that adipocytes secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway
To determine whether adipocytes affect the response of OvCa cells to chemotherapeutic drugs, adipocyte conditioned medium (Adi_CM) was collected from mature human adipocytes
Summary
Ovarian cancer (OvCa) is the most lethal cancer of the female reproductive system and the fifth leading cause of cancer death among women (www.cancer.org). The initial response rate to these drugs is over 80%, the majority of these patients will eventually succumb to resistance and cancer recurrence[4]. These sobering statistics highlight the significant and unmet need for a more thorough understanding of the driving mechanisms underlying chemoresistance and the development of better therapeutics to conquer this clinical challenge. Stromal cells from the adipose tissue of obese individuals have been reported to enhance the proliferation, migration and chemoresistance of OvCa cells[8,9]. We found that adipocytes secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Given the association between obesity, increased risk of OvCa12–14 and shorter survival in OvCa patients[15,16,17,18,19], this study suggests a mechanistic link between obesity and ovarian cancer
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